To Preserve Is Not to Select

Epilogue To Preserve is Not To Select

His nature was too large, too ready to conceive regions beyond his own experience, to rest at once in the easy explanation, ‘madness,’ whenever a consciousness showed some fullness and conviction where his own was blank. George Eliot (1876) [1]

Librarians, booksellers and publishers like books that can be conveniently classified. Books on science go on one shelf. Books on science politics go on another [2, 3]. Most students encounter science first, and read books that give no inkling of the underlying politics. This has been described as “… an enormous problem of which students, or people who look only at standard textbooks and sanitized histories of science, are usually unaware. … You get the impression that the history of science is a totally progressive, orderly, logical development of ideas” [4]. To some extent the science literature has tended to become a pat-on-the- back literature. To pass the peer-review gate, authors are inclined to paint a rosy picture, avoid controversy, and positively emphasize the work of possible gatekeepers. An exception is where controversy is exploited in a holier- than-thou literature that attempts to slip flawed arguments by the reader, while criticizing easy targets (such as people who are no longer alive), and admonishing the reader to avoid unsavoury authors who try to slip flawed arguments by. Students will inevitably learn about science politics in their later years if they become engaged in one of the most exciting aspects of science – the construction of hypotheses based on prevailing knowledge, and the making of discoveries that extend or refute that knowledge.

Percepts All scientific knowledge rests on hypotheses. Immanuel Kant argued that percepts without concepts are blind [5]. This point was also made by physiologist John Scott Haldane when writing in 1891 about his uncle, John Bur- don Sanderson, a mentor to Romanes [6]:

D.R. Forsdyke, Evolutionary Bioinformatics, DOI 10.1007/978-1-4419-7771-7, 391 © Springer Science+Business Media, LLC 2011 392 Epilogue

[He] would say ... that he is very tolerant about theories -- [but] that what really tells is facts. But then what are facts that are essential? It’s the theory that determines that. I would simply disregard as trivial and misleading heaps of things which he considers essential, and vice-versa. And even the simplest ‘facts’ are expressed - perceived - through theory. We perceive facts in the context of theory. Theories themselves, until the evidence becomes overwhelming (e.g. the theory that the earth is not flat), are unsubstantiated theories, or mere hypotheses. In an ideal world, competing hypotheses would be dispassionately analyzed and the selection of one rather than another would be made with much diffidence (see Appendix 3). Darwin in 1868 set the standard [7]: “It is a relief to have some feasible explanation of the various facts, which can be given up as soon as any better hypothesis is found.”

Torch Passed But we do not live in an ideal world. In an ideal world, the ideas advanced by Gregor Mendel in 1865 would have been selected by scientists worldwide as a basis for further experimentation. By 1870 the ideas would have entered university-level biology curricula and students at Cambridge, such as Ro- manes and Bateson, would have read Mendel along with their Darwin. Yet, as has been told many times, had Mendel never lived progress in genetics would not have been much affected [8]. Thankfully his work was preserved or we would not now know of it. But, alas, preservation does not necessarily lead to selection. At least, in the years before the independent discovery of Mendel’s laws in 1900, his work was not castigated: For historians there remains the baffling enigma of how such distinguished biologists as …W. Bateson … could rest satisfied with such a crassly inadequate theory. ... The irony with which we must now read W. Bateson’s dismissal of Darwin is almost painful. This remark in 1983 by Richard Dawkins, deservedly one of the most influ- ential scientists of our times, is representative of the multiplicity of attacks on William Bateson that occurred both before and after his death in 1926 [9]. It cannot be said that progress in genetics would not have been affected had Romanes and Bateson never lived. Their many contributions have been acknowledged and extended. However, Bateson’s detractors repeatedly pro- claimed that, through his refusal to accept the conventional genic wisdom, he had delayed progress in genetics. I have argued both here and in my other books that, to the contrary, Bateson was light-years ahead of his contempo- raries and of many who came after. It is his detractors who may have delayed progress [10, 11]. Nevertheless, the Batesonian torch was passed through the To Preserve is Not To Select 393 twentieth century by Richard Goldschmidt, by Gregory Bateson, by Michael White, and, with qualifications, by paleontologist Stephen Jay Gould. In an article entitled “The Uses of Heresy,” Gould in 1982 introduced a reprint of Goldschmidt’s classic text The Material Basis of Evolution. Here Gould described “the counterattack” of the neo-Darwinians that included his Harvard colleague Ernst Mayr’s despair at the “total neglect” by Gold- schmidt of the “overwhelming and convincing evidence” against his ideas [12]. In Gould’s opinion Goldschmidt “suffered the worst fate of all: to be ridiculed and unread” [Gould’s italics], although his “general vision” was held to be “uncannily correct (or at least highly fruitful at the moment),” and “interesting and coherent, even if unacceptable today.” In 1980 Gould himself had came close to embracing the Batesonian- Goldschmidtian argument in an article in the journal Paleobiology entitled: “Is a new and general theory of evolution emerging?”[13]. But, after a two decade struggle with both the evolution establishment and cancer, Gould recanted, while still maintaining “a hierarchical theory of selection.” In his The Structure of Evolutionary Thought, published shortly before his death in 2002, he wrote [14]: I do not, in fact and retrospect (but not in understatement), regard this 1980 paper as among the strongest … that I have ever written … . I then read the literature on speciation as beginning to favor sympatric alternatives to allopatric orthodoxies at substantial relative frequency, and I pre- dicted that views on this subject would change substantially, particularly towards favoring mechanisms that would be regarded as rapid even in microevolutionary time. I now believe that I was wrong in this prediction. Generally courteous when responding to those who did not share his evolutionary views, Gould, like Romanes a century earlier, characterized his many opponents as “ultraDarwinian” fundamentalists, to be contrasted with his few “pluralist” supporters. There are remarkable parallels between Gould and Romanes [15, 16]. Both were of the establishment and center-stage. Steeped in the substance and history of evolutionary science, their writings were welcomed by the leading journals of their days. Both wrote prolifically for the general public, as well as for scientists. Both faced attacks from the very top of their profession – Romanes from Huxley, Wallace Thiselton-Dyer and Lankester – Gould from Dawkins, Mayr and Maynard Smith. Sadly, both were stricken with cancer in their forties. A difference was that, with modern therapies, Gould survived another two decades, whereas Romanes died at age forty-six. Furthermore, Romanes never recanted and, I suspect, never would have, even if given extra time. Gould was strongly tested in 1995 by John Maynard Smith, the “Dean of British ultra-Darwinians” [17]: 394 Epilogue

Gould occupies a rather curious position, particularly on his side of the Atlantic. Because of the excellence of his essays, he has come to be seen by non-biologists as the pre-eminent evolutionary theorist. In contrast, the evolutionary biologists with whom I have discussed his work tend to see him as a man whose ideas are so confused as to be hardly worth bothering with, but as one who should not be publicly criticized because he is at least on our side against the creationists. All this would not matter, were it not that he is giving non-biologists a largely false picture of the state of evolutionary theory. In the USA Mayr protested that Gould and his allies “quite conspicuously misrepresent the views of [biology’s] leading spokesmen.” Other evolutionists were less restrained [18]: Evolutionary biology is relevant to a large number of fields – medicine, neuroscience, psychology, psychiatry, cognitive science, molecular biology, etc. – that sometimes have an impact on human welfare. Many scientists in these fields look to Gould, as America’s most famous evolutionist, for reliable guidance on his field, and so the cumulative effect of Gould’s ‘steady misrepresentation’ has been to prevent the great majority of leading scientists in these disciplines from learning about, or profiting from, the rapid series of advances made in evolutionary biology over the last thirty years. It seems not to have occurred to these critics that if Gould had, in fact, provided “reliable guidance,” then it will be their “steady misrepresentation” that will have negatively impacted human welfare. While some biohistorians have expressed dissatisfaction with the prevailing orthodoxy [19, 20], following Gould’s demise it was left largely to scientists such as Patrick Bateson (a relative of William and Gregory) and myself, to bear the torch onward into the twenty first century [10, 11, 21]. The task is now a little easier because, as has been shown here, we can begin to flesh out the Batesonian- Goldschmidtian abstractions in both informatic and chemical terms.

Voting with Facts The ground was well prepared when Watson and Crick presented their model for DNA structure in 1953. The comments of Muller and Wyatt (Chapter 2) show that the possibilities of a helix and base-pairing were “in the air.” The time was ripe. The model soon won wide acceptance. However, many new hypotheses are not so readily accepted. Another man was convinced that he had the mathematical key to the universe which would supersede Newton, and regarded all known physicists as conspiring to stifle his discovery and keep the universe locked; another, that he had the metaphysical key, with just that hair’s-breadth of difference from the old wards which would make it fit exactly. Scattered To Preserve is Not To Select 395

here and there in every direction you might find a terrible person, with more or less power of speech, and with an eye either glittering or preter- naturally dull, on the lookout for the man who must hear him; and in most cases he had volumes which it was difficult to get printed, or if printed to get read. These words of Victorian novelist George Eliot, who knew Romanes, and almost certainly knew of Butler, were written three decades before Einstein superseded Newton with his special theory of relativity [1]. Acceptance of scientific ideas can be seen as a struggle between two voting democracies – the democracy of the people, and the democracy of the facts. A scientific theory comes to be ‘accepted’ when a major proportion of the ‘experts’ in the field agree that this should be so. This is a true democracy of “the people” in the sense that, since all democracies contain ‘non-experts,’ namely those who are insufficiently qualified to have a vote (e.g. children), then their vote is assigned implicitly to those who are deemed to be qualified. However, often a theory appears to be consistent with certain facts and in- consistent with others. In the mind of the theoretician the facts themselves vote. Theoreticians embrace theories that are consistent with the most facts. Indeed, theories are usually elaborated in the first place to explain facts that seem discordant (i.e. are paradoxical). In many cases it is likely that a theoretician first finds an explanation for a few facts. As the theory develops, more and more facts fall into line (i.e. vote positively). Predictions are then made, and further facts are found that add to the positive vote. Thus, even before attempting publication or seeking experimental support, the theoretician is confronted with an array of voting facts. Even if the votes of the experts end up not supporting his/her theory, the theoretician can still affirm the probable correctness of the theory to the most significant critic – his/her doubting self – based on the voting of the facts. Thus, a disconnect can arise between the theoretician and his/her peers. As described in Chapter 1, Romanes was unable to follow Butler’s conceptual leap that heredity was due to stored information (memory). Today, this seems rather obvious. But, much in awe of Darwin, in 1881 Romanes, aged thirty-three and already a Fellow of the Royal Society, scathingly reviewed Butler’s Unconscious Memory and scoffed at the exposure of the flaws in Darwin’s theory [22]: Now this view … is interesting if advanced merely as an illustration; but to imagine that it maintains any truth of profound significance, or that it can possibly be fraught with any benefit to science, is simply absurd. The most cursory thought is sufficient to show … . One reason for this, of course, is that each person on this planet is somati- cally different from every other person, and occupies a unique position in time and space. Each person has a unique perspective. Einstein worked in a 396 Epilogue

Swiss patent office when time zones were being established and there was an enormous interest in accurate time-keeping. Switzerland was the center of the clock-making industry. It is likely that he reviewed many submissions on the synchronization of clocks, a major principle underlying relativity theory [23]. This focused his mind in a way denied to his peers in their academic ivory towers. It is to their credit that they did not bar publication of his work in 1905 and, within a decade, most came to recognize its worth. Yet, in all probability, Einstein would still have believed his theory correct, even if his peers had not accepted it. Butler was also far from the ivory tower. By the time of his death in 1902, the Victorian establishment had scarcely moved an inch towards acknowledging his contribution. This annoyed, but did not overly disconcert [24]: If I deserve to be remembered, it will be not so much for anything I have written, of for any new way of looking at old facts which I may have suggested, as for having shown that a man of no special ability, with no literary connections, not particularly laborious, fairly, but not supremely, accurate as far as he goes, and not travelling far either for his facts or from them, may yet, by being perfectly square, sticking to his point, not letting his temper run away with him, and biding his time, be a match for the most powerful literary and scientific coterie that England has ever known. Yes, a powerful coterie, but at heart a kindly one, not malicious. George Bernard Shaw, who counted himself as among “the best brains” that supported Butler put it this way [25]: Darwin, a simple-souled naturalist with no comprehension of the abyss of moral horror that separated his little speciality of Natural Selection from Butler’s comprehensive philosophic conception of Evolution, may be pardoned for his foolish estimate of Butler as ‘a clever unscrupulous man,’ and for countenancing the belittling of him by Huxley and Ro- manes that now seems so ridiculous. They really did not know any better.

False Leads? Quick acceptance of the double helix model soon led to prediction of the existence of mRNA. But here there was a prominent decoy – rRNA – that provided powerful ammunition to the skeptics. Crick noted [26]: It is astonishing how one simply incorrect idea can envelop the subject in a dense fog … the assumption that the ribosomal RNA was the messenger RNA. … Only the gradual accumulation of experimental facts that appeared to contradict our basic idea could jolt us out of our preconception. Yet we were acutely aware that something was wrong and were continually trying to find out what it was. It was this dissatisfaction with our ideas that made it possible for us to spot where the mistake was. If we had To Preserve is Not To Select 397

not been so conscientious in dwelling on these contradictions we should never have seen the answer. Judicial wisdom may not be displayed even by people of scientific emi- nence who, earlier in their careers, have themselves failed to convince skeptics. Several years after Einstein’s seminal paper on special relativity, Max Planck and other distinguished physicists, while embracing relativity, incor- rectly cautioned that Einstein “may sometimes have missed the target in his speculations, as, for example, in his hypothesis of light quanta” (which, of course, was correct) [4]. Planck’s own ideas on the second law of thermodynamics had not been appreciated by Helmholtz, whose ideas, in turn, had also not been recognized. Indeed, Helmholtz appreciated that “new ideas need the more time for gaining general assent the more really original they are” [27], but he may here have been thinking more of the originality of his own ideas than those of others! The work of the seventeenth century polymath Robert Hooke was condemned to oblivion because of “the implacable enmity of Newton …. But deeper than this is perhaps … that Hooke’s ideas … were so radical as to be inassimilable, even unintelligible, to the accepted thinking of his time” [28]. In this way it is argued that peers are obliged to discard “premature” claims, to avoid being overwhelmed by false leads [29]. So if a theoretician’s peers do not accept, what is an impartial observer to do? In the words of Butler in 1890 [22]: We want to know who is doing his best to help us, and who is only trying to make us help him, or bolster up the system in which his interests are invested. … When we find a man concealing worse than nullity of meaning under sentences that sound plausibly enough, we should distrust him much as we should a fellow-traveller whom we caught trying to steal our watch. Similarly, a century later Dawkins noted [30]: It’s tough on the reader. No doubt there exist thoughts so profound that most of us will not understand the language in which they are expressed. And no doubt there is also language designed to be unintelligible in order to conceal an absence of honest thought. But how are we to tell the difference? What if it really takes an expert eye to detect whether the emperor has clothes? Butler had a solution [22]: There is nothing that will throw more light upon these points than the way in which a man behaves towards those who have worked in the same field with himself … than his style. A man’s style, as Buffon long since said, is the man himself. By style, of course, I do not mean grammar or rhetoric, but that style of which Buffon again said that it is like happiness, and vi- 398 Epilogue

ent de la douceur de l’âme. … We often cannot judge of the truth or falsehood of facts for ourselves, but we most of us know enough of human nature to be able to tell a good witness from a bad one. More specifically, four questions need to be asked. Is the theoretician sane? Is the theoretician objective? Is the theoretician honest? Does the theoretician have a credible track record in the field? A negative answer to these questions will not disprove the theory. A positive answer, however, should serve to counter a negative vote from alleged experts. For Bateson and Goldschmidt, the answers are quite positive. Their de- meanors, relationships and writings attest to their sanity, objectivity and hon- esty, the latter being most evident towards the person they would most likely deceive, themselves. Like Romanes before them, having been immersed in evolutionary science for many decades, they were both very well prepared. Yet, like Romanes before them, they were denied the benefit of the doubt and were subjected to personal attacks. George Eliot wrote [1]: Like Copernicus and Galileo, he was immovably convinced in the face of hissing incredulity; but so is the contriver of perpetual motion. We cannot fairly try the spirits by this sort of test. If we want to avoid giving the dose of hemlock or the sentence of banishment in the wrong case, nothing will do but a capacity to understand the subject-matter on which the im- movable man is convinced, and fellowship with human travail, both near and afar, to hinder us from scanning any deep experience lightly. People are not impartial. As suggested here and elsewhere [3], people act from a variety of motives other than that of seeking the truth. They will not diversify and hedge their bets – an admonition that even those in Wall Street are prone to forget. And sometimes, despite the best intentions, they just do not seem to find time to do their homework. Writing in 1932 to the US ge- neticist Thomas Hunt Morgan, Ronald Fisher noted [31]: One of the chief reasons why, in spite of raising so much dust, we are not making in this generation more rapid progress, is that we do not really give ourselves time to assimilate one another’s ideas, so that all the difficult points, the things really worth thinking about, have to be thought out independently, with great variations in efficiency and success, some hun- dreds of times.

Marketing While Madison Avenue-style blandishments convince that round pegs fit square holes, and square round, the bubble of complacency grows and grows. The conceptually challenging, seemingly abstract, arguments of Romanes, Bateson and Goldschmidt denied Darwinian dogma. For this they were dis- missed by generations of biologists bewitched by genes and all that their To Preserve is Not To Select 399 marketers promised. With overwhelming rhetoric to the contrary, we were slow to appreciate the deep truths they were attempting to convey [10, 11, 15]. And so on into the twenty first century. Scientific understanding continues to advance at a pedestrian pace with much waste of time and energy, and of public and private funds. As indicated in the Prologue, commercial interests continue to exert an undue influence on what science is supported and published. A Canadian, bioethicist comments [32]: Conditions that are attached to government funding can affect the pur- poses and values upheld, especially when those conditions require academic-industrial partnerships for research to be eligible for funding, as in the case of the Canadian government’s $300 ... million investment in a series of genomics research centres (Genome Canada). Structuring funding in this way leaves out the funding of research that will not result in mar- ketable products, and excludes those researchers who undertake it. It should not be imagined that the situation will easily change. In 1931 the author of Brave New World, Aldous Huxley (a grandson of Thomas Huxley), wrote to Fisher [33]: The really depressing thing about a situation such as you describe is that, the evil being of slow maturation and coming to no obvious crisis, there will never be anything in the nature of a panic. And as recent events only too clearly show, it is only in moments of panic that anything gets done. Foresight is one thing: but acting on foresight and getting large bodies of men and women to accept such action when they are in cold blood – these are very different matters. Thus, the western democracies, driving to ever increasing prosperity with individuals liberated to explore and indulge their perceived interests and de- sires, appear somewhat like headless monsters. Such a situation appears infi- nitely to be preferred over a totalitarian alternative, provided there can be appropriate feedbacks from periphery to center so that things do not spiral out of control. Sometimes the ‘bubbles’ burst rapidly as when panics seize Wall Street. But more often, as noted above, there is “no obvious crisis” – people with AIDS, cancer, malaria or schizophrenia slip quietly away, one at a time. We all know the remedy. The bursting of such bubbles requires informed individuals with the courage peacefully to challenge the conventional wisdom, open-minded information gatekeepers, a free press, and an attentive and re- sponsive executive that is attuned to history.

Joining the Dots The “intelligence failure” of September 11th 2001 occurred while the first edition of this book was in preparation. It turned out that, prior to the event, 400 Epilogue there had been substantial clues, but the ‘Mendels’ and ‘Butlers’ in government agencies had been overlooked. The ‘authorities’ had failed to sift and weigh. They had failed to ‘join the dots.’ Likewise, as argued here, the bio- medical research enterprise, while “concealing difficulties and overlooking ambiguities” has sometimes failed similarly. Sadly, there has been little recognition of this. Indeed, the very opposite, as the outcry of the complacent against Gould revealed. Hailing the sequencing of the human genome as again demonstrating the vigor of free-market systems, commentators can contrast this with the attack on genetics by Trofim Lysenko who in the 1930s won the support of Joseph Stalin, and sent his competitors to their deaths [34]. Yet few are aware of the emergent ‘new Lysenkoism’ in the West that, while sparing their bodies, has forced academic suicide (i.e. loss of research funding, tenure, etc.,) on those who could see beyond their noses and refused to embrace the prevailing orthodoxy [2, 3]. Is “suicide” too strong a word? Well, “It is suicidal” was how Marshall Nirenberg’s plan (ultimately successful) to decipher the genetic code was greeted by a colleague at the US National Institutes of Health in 1959 [35]. While Romanes, a friend of the editor of Nature, had little trouble getting his anonymous editorials and signed articles accepted [36], in the early decades of the twentieth century William Bateson battled the peer-review gatekeepers who controlled access to publication. He had to content himself with the less visible Reports to the Evolution Committee of the Royal Society. But- ler had to self-publish most of his works on evolution, and negative reviews by the Victorian establishment ensured that he would suffer repeated finan- cial losses. In his early days, Fisher submitted a paper on the probable error of the correlation coefficient to the journal Biometrika. The Editor, the bio- metrician Karl Pearson, rejected it since he was “compelled to exclude all that I think is erroneous on my own judgement, because I cannot afford controversy” [37]. Chargaff himself was subject to the “hissing incredulity” of the funding agencies. As an innovative and vigorous experimentalist (he lived to be 96), it is likely that knowledge of the base compositional regularities he described would by now have been much further advanced had he not been forced into retirement [2]. And, just as it is the victors in war who write the history books, so it can be the successful marketers and their disciples who write the history of science. Like the hero in Beau Geste who propped up dead soldiers to suggest that the fortress was well defended [38], so the marketers – biology’s “leading spokesmen” – tend to prop up the careers of those disciples who will defend their views, even in the face of mounting evidence to the contrary. To Preserve is Not To Select 401

Cogito Ergo …? It is my hope that, having completed this book, you will have captured my enthusiasm for EB and my belief that studies in this area will greatly advance progress towards solutions to major problems of humankind. But this Epi- logue implies caution. If you intend to engage in this area, be prepared for difficulties. If you have a penchant for joining the dots, and find that you can see beyond your nose, then be prepared for a hidden life with quick passage to an academic tomb inscribed cogito ergo non sum. Yet, there is a ray of hope suggesting that times may now be different from when Aldous Huxley penned those depressing words above. Through the Internet amazing new lines of communication have opened to all, and developments in search-engine design promise a sifting and manipulation of information that would have been unimaginable to our fathers. The headless monster (Adam Smith would have called it “the invisible hand”) of our bio- medical/industrial enterprise, has generated more data than it can handle. This is preserved in open databases worldwide. Inspired programmers are writing ‘open source’ software packages that can be downloaded with a click. So, if we so decide, that which is preserved can be selected with ease. The playing field is being leveled in strange ways. But ease of selection does not ensure that selection will be wise. Canadian chemist John Polanyi points out that although now, more than ever before, information is freely available to all, it “only appears to be freely available to all. In fact, it is available only to those who understand it’s meaning, and appreciate its worth” [3]. Hopefully, the present book will help you understand its meaning and worth. Voltaire in 1770 wrote “On dit que Dieu est toujours pour les gros bataillons” [39]. Today, les petits bataillons may be similarly favored. Even so, the difficulties will be great, and you may try, and fail, as did George Eliot’s sad figure, Casaubon, in her novel Middlemarch. But, unlike Casaubon, through trying you may come to understand, and hence become able to communicate, the wisdom of others, so that the works of tomorrow’s Mendels, Herings, Butlers, Romanes, Batesons, Goldschmidts and Chargaffs will not go unrecognized. Let George Eliot close [40]: Her full nature … spent itself in channels which had no great name on the earth. But the effect of her being on those around her was incalculably diffusive: for the growing good of the world is partly dependent on unhis- toric acts; and that things are not so ill with you and me as they might have been, is half owing to the number who live faithfully a hidden life, and rest in unvisited tombs.

Appendices

Appendix 1

What the Graph Says

Since the probability of two bombs being on the same plane is very low, the wise statistician always packs a bomb in his/her luggage. Anonymous (before the modern era of airport security)

Evolutionary bioinformatics (EB) requires the handling of large amounts of sequence data, sometimes from multiple biological species. This is greatly assisted by plotting the data points on a graph. The points are often widely scattered, and the volume of data – sometimes many thousands of points – can seem overwhelming. Fortunately, there are software packages (like Mi- crosoft Excel) that will plot the points and draw the statistically best lines through them. The graphs can sometimes be understood immediately without resort to numerical analysis. But confidence increases when visual interpretations are numerically confirmed. Thus, throughout this book graphical displays include values for slopes of lines, squares of the correlation coefficients (r2), and probabilities (P). These capture key features of what might otherwise seem a hopeless jumble of points. Out of a cloud meaning emerges, sometimes discerned only as faint, but statistically significant, signals. Often lines are linear (rectilinear), but sometimes they are curved (curvi- linear). Often rectilinear lines are tilted, but sometimes they are horizontal. Sometimes no linear interpretation is evident, but clusters of points can be demarcated from others by drawing circles around them. Without resort to a statistics text, the essence of what the various values tell us can be shown by constructing dummy graphs and then applying a standard software package.

Horizontal Lines Table 21-1a shows a spreadsheet with X-axis values increasing from 1 to 20. Four sets of Y-axis values were preselected as detailed below. 406 Appendix 1

Table 21.1. A spreadsheet of dummy data values (a) for generation of graphical plots that are either horizontal (columns 1 and 2), or sloping (columns 3 and 4). It is intended that, around the line that best fits the points (as determined by a standard computer program), there be either a small scatter of points (columns 1 and 3), or a large scatter of points (columns 2 and 4). Various statistical parameters are shown (b) below the related columns. Scatters around regression lines are measured as standard errors of the estimate (SEE) or standard errors of the mean (SEM) What the Graph Says 407

In Table 21.1 Y-axis values for four plots of different sets of Y values against the X values are displayed in columns 1 to 4. Numbers were placed in the first two Y columns with the intention of plotting two horizontal lines that would cross the Y-axis at a value of 6 (i.e. Y0, the value for Y when the X value was zero, would be 6). For column 1, the numbers were allowed to deviate very little from the mean of 6. Thus, in the first row, 6 was entered. Then, in the second row, 5.9 was entered. Then, to compensate for this, so that an average of 6.0 was sustained, in the third row 6.1 was entered. This was continued to generate 20 values for Y with minima no lower than 5.8 and maxima no higher than 6.2. For column 2, the numbers were allowed to deviate further from the mean of 6. Thus in the second row 5 was entered. To compensate for this, so that an average of 6 was sustained, in the third row 7 was entered. This was continued to generate 20 values for Y with minima no lower than 4, and maxima no higher than 8. The computer was then asked to plot the two sets of Y values against the set of X values. The resulting graph (Fig. 21.1) shows two horizontal lines (“regression lines”), which are so close that they cannot be distinguished by eye. Values from column 1 (open circles) sit close to the lines. Values from column 2 (gray circles) are more widely scattered. The statistical read-out from the computer is shown below the corresponding columns in Table 21.1. As expected, the averages (arithmetical means) of the two sets of twenty Y values are both 6. A measure of the degree of scatter about the regression lines is provided by the characteristic known as the standard error. As expected, the values in column 1 are less scattered about the regression line than the values in column 2 (0.133 versus 1.333). The squares of the correlation coefficient (r2; sometimes called the coefficient of determination) are essentially zero in both cases. This means that no part of the variation between the twenty data values for Y (the “dependent variable”) can be attributed to the changes in the twenty data values for X (the “independent variable”). Both sets of numbers vary (in column 2 more than in column 1). But, whatever caused that variation, it was not related to X (as far as we can tell from the numbers at our disposal). Being a near horizontal line, the slope value (change in Y value per unit X) is very close to zero (a = 0.003 in each case). That this slope value is not significantly different from zero is shown by the associated probability values (P), which normally range over a scale from zero to one. The P values are both 0.954 showing that, for the number of data points available, it is most probable that there is no significant difference from a slope value of zero. By convention, P values must be less than 0.05 to establish likely significance. Finally the values for the intercept on the Y-axis (Y0 values) are both 6, as expected. 408 Appendix 1

Fig. 21.1. Computer-generated lines that best fit the plots of the data shown in Table 21.1. Open circles (column 1 data); gray circles (column 2 data); open circles with central dot (column 3 data); gray circles with central dot (column 4 data). There are two horizontal lines for columns 1 and 2 and two sloping lines for columns 3 and 4, but the line pairs are so close that they cannot be distinguished (i.e. they overlap)

Tilted Lines It was next intended to tilt the two horizontal lines so creating two new lines differing from the originals in slope and in intercept at the Y-axis (Y0). Accordingly, values were generated for columns 3 and 4 by adding increasing numbers to the values in columns 1 and 2, respectively (Table 21.1). Thus, zero (0) was added to the numbers in the first row (columns 1 and 2), so the numbers both remained at 6 (columns 3 and 4). Then, 1 was added to the numbers in the second row (columns 1 and 2) to generate values of 6.9 and 6.0 for columns 3 and 4, respectively. Then, 2 was added to the numbers in the third row to generate values of 8.1 and 9.0, respectively. Then, 3 was What the Graph Says 409 added to the numbers in the fourth row to generate values of 8.8 and 7.0, respectively. This was continued to fill columns 3 and 4, each with twenty numbers. The resulting computer plots (Fig. 21.1) show two new sloping lines (which are again indistinguishable from each other by eye). They retain the same scattering of points as in the horizontal plots from which they were derived. As expected, the mean values for the sets of numbers in columns 3 and 4 are greater than the corresponding sets in columns 1 and 2 (Table 21.1b). But, since the scatters about the regression lines are unchanged, the standard errors are unchanged. The standard errors for columns 1 and 3 are identical. The standard errors for columns 2 and 4 are identical. On the other hand, the r2 values, which like P values range from zero to one, are 0.999 and 0.951, respectively. Thus, in the case of the plot with less scatter of the points around the regression line (Y values from column 3), much of the variation among these values can be explained on the basis of the X data values. Thus, the r2 value of 0.999 means that essentially 100% of the variation among the twenty Y values correlates with the underlying variation among the twenty X values. In the case of the plot with more scatter of the points around the regression line (Y values from column 4), much of the variation between these data values can again be explained on the basis of the X data values. However, in this case the r2 value is 0.951 showing that, while 95% of the variation among the twenty Y values correlates with the underlying variation in the twenty X values, 5% of the variation might relate to another factor, or other factors. The slope values (both 1.003) are now no longer close to zero. Further- more, the associated P values (<0.0001) affirm that the slope values are likely to be significantly different from the horizontal (i.e. there is only a very low probability that the slope values are not significantly different from zero). The Y0 values show that both slopes extend back (extrapolate) to cross the Y axis when Y is equal to 5. Thus, all four lines intercept (have a common value) when X is 1 and Y is 6.

Curved Lines In Figure 21.1 the data points are economically fitted to straight lines, as is the case with many graphs in this book. Each slope can then be described mathematically by a single value (often designated as “a” in what is known as a “first order” relationships). However, sometimes the lines curve (e.g. Chapter 14). In these cases, description of the slopes requires further values (“a” and “b”) in what are known as a “second order” relationship). For dis- section of more complicated relationships, procedures such as “principle component analysis” and “best subsets regression” are available in software packages (e.g. Matlab, Minitab). Table 10.1 is an example of the latter. 410 Appendix 1

No Lines Sometimes data points form a cluster and no linear relationship can be discerned. In this case the points can be represented as a single central point with some measure of their scatter around that point. The central point is determined by the two values for the means of the X-axis and Y-axis values. This point is surrounded by an oval, the limits of which are determined by the scatters of X and Y values along the corresponding axes. For this the corresponding standard errors provide a measure (e.g. Fig. 18.2). There are computer programs that can examine a large cluster of points and determine whether it can be divided into sub-clusters. Thus, although discriminated sets of points were plotted in Figure 18.2a, we could have plotted all the points without discrimination and then could have asked a computer program to attempt to independently cluster them.

A Caution Huxley in 1864 noted “three classes of witnesses – liars, damned liars, and experts.” While retaining its truth, in modern time this has further mutated to three classes of lies – “lies, damned lies, and statistics.” There are many reasons to be cautious about statistics. My favorite statistician story is that of the statistician who, after war had ravaged Holland, noted a strong correlation between the subsequently rising birthrate and the return of storks to nest on the housetops. However elegant the mathematics, if applied without an awareness of “the big picture,” statistics can be very misleading. Of concern to the student of bioinformatics is that sequences are now available in GenBank because, at some point in time, people decided to sequence them. Sequencers being of the species Homo sapiens, they tended to prefer DNA either from Homo sapiens, or from species of economic importance to Homo sapiens, which includes species that are pathogenic for Homo sapiens and his dependent species (domesticated animals and cultivated plants). Thus, the sequences currently in databases are far from being a random sample. We must keep this in mind when selecting sequences for our studies, and when interpreting results.

Appendix 2

Scoring Information Potential

A man who knows the price of everything and the value of nothing. Oscar Wilde, Lady Windermere’s Fan

Information scientists measure information as binary digits or “bits” (Chap- ter 2). The information value of each unit in a sequence segment depends on the number of types of possible unit that are present in the segment (e.g. base composition), not on the way the units are arranged (e.g. base order). Ac- cording to their compositions, different segments can be scored for their respective potentials to carry order-dependent “primary” information. The same segments retain their potentials to carry composition-dependent “secondary” information. In spoken information the text can be regarded as primary, and the accent or dialect can be regarded as secondary (Chapter 3).

Two Units If, in a hypothetical nucleic acid sequence that can contain only two types of base, the bases are distributed randomly but with equal probability (i.e. at a particular position the uncertainty as to which base is coming next is maximum), then each base adds 1 bit of potential base order-dependent information. Thus, 2 = 21. The left 2 refers to the number of bases. The right 2 refers to the type of decisions (binary yes/no decisions; Chapter 2). The 1 bit on the right side of the equation is referred to both as the “exponent” of the 2 on the right side of the equation, and as the “log,” or “logarithm,” of the 2 on the left side of the equation. If only one of the two available bases is present in a segment (“window” in the sequence) there is no uncertainty as to which base is coming next, and each base adds 0 bits of potential base order-dependent information (1 = 20). So variation along a nucleic acid sequence, which contains only one or two types of base, can be assessed in terms of its local content of potential base order-dependent information in sequence windows on a log scale scoring 412 Appendix 2 from 0 to 1 for each base (i.e. the number of bits in a window is equal to the logarithm to the base 2 of the number of available base types in that window). A ten base window consisting of only one base (e.g. AAAAAAAAAA) would score zero (10 x 0). A ten base window consisting of equal quantities of the two bases (e.g. ATTATAATAT) would score 10 (10 x 1). This score would not change if the order of the bases was varied.

Four Units Along similar lines, if the four bases of a natural nucleic acid sequence are distributed randomly, but with equal probability, along a sequence (i.e. at a particular position the uncertainty as to which of the four bases is coming next is maximum), then each base adds 2 binary digits (bits) of potential base order-dependent information (4 = 2 x 2 = 22). If only one base is present in a sequence segment, there is no uncertainty and each base adds 0 bits of potential base order-dependent information (1 = 20). Again, the left side of the equation refers to the number of bases, and the exponent of 2 on the right side refers to the number of binary (yes-no) decisions required to distinguish between those bases at a single position in the sequence segment. Here, potential base order-dependent information content (the exponent) is on a scale from 0 to 2. A nucleic acid sequence containing one to four bases can be assessed in terms of its local content of potential base order-dependent information on a log scale scoring from 0 to 2 for each base (i.e. again, the number of bits is equal to the logarithm to the base 2 of the number of bases).

Twenty Units A protein, with a structure even more elaborate than that of a nucleic acid, is hardly susceptible to analysis in these terms. Nevertheless, similar reason- ing can be applied to protein sequences with one to twenty amino acids. Here the scale is from 0 (1 = 20) to 4.322 (20 = 24.322). Following the binary decision-making principle, one begins by dividing the pool of twenty amino acids into two equal groups. A hypothetical informed respondent, on being asked whether a certain pool contains the next amino acid, replies either positively or negatively, and one has reduced the number of possibilities to ten. This ten is then divided into two equal groups of five, for a second round of interrogation. Third, fourth and, sometimes, fifth, interrogations follow. Since five amino acids do not divide into two equal groups, the number of interrogations is not unitary, but has to occur, on average, 4.322 times (i.e. on average, 4.322 binary (yes-no) decisions are needed to specify which of the twenty amino acids occupies the next position in a protein sequence). The number of bits is equal to the logarithm to the base 2 of the number of types of amino acid in a window. Scoring Information Potential 413

Meaning The above calculations display a quantitative aspect of information. Given the number of each type of base in a DNA segment (its base composition) we can determine the segment’s potential to carry different base order-dependent messages. Its potential is low if the segment contains only one of the four bases. Its potential is maximized if the segment contains equal proportions of the four bases (Chapter 14). However, of all the potential base order- dependent messages, only those of a small subset are likely to convey meaning (i.e. they convey information that may or may not be helpful to the receiver). The existence of a message does not imply that it has a meaning. We need to distinguish sense, which informs the receiver (helpfully or unhelp- fully), from non-sense, which does not inform the receiver. Meaning requires the existence of a code through which some messages can convey meaning. The same code may be applied to other messages, but a meaning may not emerge. Sometimes meaning requires recognition of base composition alone (i.e. the code maps different meanings to different base compositions). How- ever, often critical to meaning is base order. This is a qualitative aspect of potential information. Take, for example, various three-unit message sequences composed of two unit types – say 9 and 1. At each position in each sequence there is either a 9 or a 1, so there are 3 binary decisions to be made. There are 2 x 2 x 2 = 23 = 8 alternatives (i.e. the length of the sequence is equal to the logarithm of the number of possible messages). These eight messages are 999, 991, 919, 199, 911, 191, 119, and 111. The first and last contain only one unit type. Of the remaining six (underlined), three have two nines and a one, and three have one nine and two ones. Thus, there are four composition-dependent messages – three nines (999), two nines and a one (991, 919, 199), one nine and two ones (911, 191, 119), and three ones (111). Which of the eight messages has order-dependent meaning depends on the existence of appropriate codes. Perhaps each message has a distinct meaning. Perhaps none has. 911 is a widely recognized ‘universal’ alarm call. For all I know, 191 may be the ‘pin number’ you enter when using your credit card. Thus, it is possible to distinguish general codes that are not individual- specific (i.e. they are observer-independent), and local codes that are individual specific (i.e. they are observer-dependent). However, if you passed on your pin number to your children, and they passed on the same pin number to theirs, etc., then your pin number could become more general. All organisms in our planetary biosphere are considered to have evolved from a common ancestor. This seems to predict that all biological codes should be general, as is the case with the codes we have dis- covered so far (with a few minor wrinkles). So coding studies carried out on the bacterium E. coli are helpful in understanding coding in Homo sapiens. 414 Appendix 2

A DNA sequence may be natural or artificial. A natural DNA sequence has evolved and so has distinguished itself from the large theoretical subset of DNA sequences of the same length and base composition. The entire sequence is likely to have base order-dependent biological meaning if the information channel through which it has ‘flowed’ through the generations has a limited carrying capacity. If carrying capacity is largely unlimited then the unlikely notion that genomes can carry many long meaningless messages for more than a few generations (Chapter 15) remains on the table. Imagine that carrying capacity in an information channel is so limited that only three units out of a set of nines and ones can be accommodated. So we can send a three-unit alarm signal (911), which can be interpreted as “primary” order-dependent information and the appropriate code applied. The same three units can also be interpreted as “secondary” composition- dependent information and an appropriate code applied. In this case, 911 is one of the set with one nine and two ones (911, 191, 119). Each of these would have the capacity to convey the same composition-dependent message (whatever that might be). Thus, if appropriate codes exist, 911 can simultaneously convey two messages. The order-dependent code (for “primary information”) allows the recipient to distinguish between a total of eight possible meanings. The composition-dependent code (for “secondary information”) allows the recipient to distinguish between a total of four possible meanings. The recipient would have to know from the context whether the encoder intended the message to be read as primary or secondary information, or both. However, given that only three units can be accommodated, what if the encoder wanted to send both an alarm signal (911) and a composition-dependent signal that to encode required three ones (111)? There would then be a conflict. The encoder could either send 911 or 111, but not both. Furthermore, 911 would give the wrong information if decoded as secondary information. 111 would give the wrong information if decoded as primary information. The encoder would have to weigh the relative importance of the two messages and decide which to send, and in which context. This, in a nutshell, is the topic of this book.

Appendix 3

No Line?

The ancient wisdoms are modern nonsenses. Live in your own time, use what we know and as you grow up, perhaps the human race will finally grow up with you and put aside childish things. Salman Rushdie. Step Across the Line (2003) [1]

In the struggle for literary existence this book may not survive to provoke the comments of future historians. In the event that it does, it is probable that, but for this appendix, they would have wryly noted that, while at the turn of the twentieth century religious extremism was the center of attention – the self- immolation of terrorists and the so-called “intelligent design” version of creationism – this book, like many other contemporary evolution texts, disre- garded the topic. Indeed, evolutionists (or rather, evolutionists that get published) tend to draw a politically-correct line between science and religion, arguing for separate, non-overlapping, domains, or “magisteria” [2, 3]. But certain approaches used by scientists can be applied to issues deemed religious, while remaining within bounds deemed scientific.

Setting the Stage Apart from the genetic information stored in our DNA, we also have non- genetic “mental” information (Chapter 1). The latter is stored in some, at the time of this writing, undefined form (Chapter 19), and we may choose to assign it to external databases, often in digital form. Human memory being limited and humans being ephemeral, each generation depends on those proceed- ing to have selected and assigned some of their non-genetic information to databases, and to have preserved it there in forms that can be accessed. Data- bases per se have not, as far as we know, acquired the ability to manipulate information in the way humans do – a function to which we give the name “consciousness.” Human consciousness keeps alive (i.e. holds in trust) what would otherwise be dead information. As Butler pointed out, it is like money in your pocket, dead until you decide to spend it. And human consciousness 416 Appendix 3 itself is kept alive by passage of DNA from generation to generation. The dependence on previous generations is of much consequence. It is an inescapable fact that your grandparents appeared on this planet before your parents, and your parents before you. Thus, your ancestors had the opportunity, which they often availed themselves of, to ‘set the stage.’ On ar- riving you found that much around you, and the accompanying admonitions, made sense. They told you not to touch the candle flame. Ooops! Won’t do that again! And like many of your six billion fellow planetary residents, you came to ask how we came to be here and, the not necessarily related question, how we should conduct ourselves during a stay that, with the passage of years, can appear increasingly brief. Having been wisely guided on less substantial issues, many of the six billion are inclined not to doubt the wisdom of ancestral answers to these two substantial ones. Salman Rushdie – whose rebellion against religious authority (reminiscent of Samuel Butler’s a century earlier) [4], led a head of state with parliamentary support to condemn him to death (issue a fatwa) [1] – put it this way: You will be told that belief in ‘your’ stories [i.e. your people’s stories] and adherence to the rituals of worship that have grown around them, must become a vital part of your life in this crowded world. They will be called the heart of your culture, even of your individual identity. It is possible that they may at some point come to feel inescapable, not in the way that truth is inescapable, but in the way that a jail is. They may at some point cease to feel like the texts in which human beings have tried to solve a great mystery, and feel, instead, like the pretexts for other prop- erly anointed human beings to order you around. And it’s true that human history is full of the public oppression wrought by the charioteers of the gods. In the opinion of religious people, however, the private comfort that religion brings more than compensates for the evil done in its name. William Bateson put it no less emphatically in 1889 having proposed mar- riage to his future wife within two weeks of their first meeting during a cul- tural trip to Dresden: For me and for most other people in this year of grace I believe the prac- tice of religion to be an outward and visible sign of inward and spiritual duplicity. Of course there are a very few men who feel things heavenly as vividly as things earthly, but they are very rare. For me to be married in a church would be acting a lie and though I love the old services as I do, the old buildings, as some of the fairest things left to us in an age of pollution and shoddy[ness], yet my feeling is that it is ours as a trust somehow from our forefathers, in which we have no part lot, and I should feel just as false if I went to Church and took credit for sanctity as I should if passed a false cheque. No Line? 417

Needless to say, the stage had been well set. They were married in a church [5]. And the stage may have been so well set that you also may have been persuaded that the two substantial questions are indeed related – namely, that the origin of planetary life came replete with instructions (“commandments”) as to how that life should be lived.

Rules of Thumb Science deals with observations such as that the sun rises in the east and sets in the west, and that the surface of the earth appears flat. As has been shown in these pages, through hypothesis, experiment, and fresh observations, scientists arrive at schemes of relationships that correspond to reality (i.e. are ‘true’) to the extent that they increase our understanding of, and hence potentially our command over, our environment. Thus, for a given set of circumstances it becomes more probable that we will correctly decide how to proceed. However, in addition to this general approach (i.e. the scientific method), there are three ‘rules of thumb’ that scientists – indeed, thinking people in general – have found to be valuable, albeit not infallible, adjuncts. The first, attributed to William of Occam (Chapter 3), is that, given a number of alternative hypotheses to explain a set of observations (facts, data, phenomena), one should first go by (i.e. have most faith in) the simplest consistent with the observations, and only turn to the more complex when the simplest has been tested and found wanting. The second is a variant of the first and is sometimes attributed to Albert Einstein. It is that one should indeed prefer the simple over the complex, but not the too simple. For example, the hypothesis that everything is a balance between the forces of good and evil can be made to explain anything. The sun rises in the east because the forces of good are supreme, and sets in the west when the forces of evil get the upper hand. You were wide awake at the beginning of a lecture because of the forces of good. You were fast asleep at the end because the forces of evil had prevailed. Finally, there is what can be called “the feather principle.” Confronted with a number of competing hypotheses (of which one is “none of the above”), be most dubious of the hypothesis that is pressed by those who have much to gain materially should the hypothesis come to be generally accepted. In other words, suspect those who may be seeking, either consciously or un- consciously, to ‘feather their own nests’ by advocating a particular hypothesis. As Butler pointed out [6]: “It is not the rat catcher’s interest to catch all the rats; and, as Handel observed so sensibly, ‘Every professional gentleman must do his best for to live’.” As discussed in Chapter 1 and the Epilogue, scientists themselves can have vested interests in particular viewpoints that may play the feathering role to the extent that their power and authority in a hierarchical system is sustained. 418 Appendix 3

This may sometimes be seen in its negative form – a failure to admit the existence of a particular, rival, hypothesis. Thus, when confronted with two rival texts authored by A and B, where A, albeit negatively, cites the previous work of B, but B, through ignorance or disdain, does not cite the previous work of A, be most dubious of B. Even if we accept the assertion that the scientific method per se cannot be applied to religious issues [2, 3], nevertheless we can still apply the three rules of thumb. The hypothesis of one, quasi-anthropomorphic, intelligent creator, accords well with Occam’s principle. Quite simply, an entity exists that understands, and can ordain, everything. You have a problem? Be as- sured that things are that way because that entity decided it should be so. Next question please! Of course, this argument contradicts the second rule of thumb. The argument is just too simple. It explains everything, yet it explains nothing. Fur- thermore, applying the feather principle, we can note that the material benefits accruing to its advocates have often been substantial. Indeed, for millennia thinking men and women who lack material resources have opted for the cloistered life where, in return for dispensations of what Karl Marx would have called “opium” to the populace, they have been left in peace to pursue whatever they might find agreeable. It is likely that Mendel took this path. The necessity for a governing Prince to simulate religiosity if he wished to continue to enjoy the benefits of his office was stressed by Machiavelli [7], and modern politicians disregard this at their peril [1]. However, the creationists do quite well in terms of the negative feather principle – their opponents tend not to cite their texts, whereas creationists tend not to reciprocate by omitting citation.

Probabilities On balance, creationism fails by the rule-of-thumb principle. But what can science offer instead? Can what science offers also resist rule-of-thumb scru- tiny? First we should recognize that, as noted by Thomas Huxley [8], it is difficult for a scientist to be a 100% atheist. A scientist, to remain credible as a scientist, must assign a probability to each member of a set of competing hypotheses. A hypothesis deemed to be most unlikely, such as that of the existence of a supreme creator of the universe, can be assigned a very low probability, but it cannot be excluded. For a scientist, a declaration that one is say, a Darwinist, merely means that, on balance, one adopts (i.e. has most faith in) Darwin’s view of the power of natural selection. Similarly, one may declare oneself to be an atheist, meaning that, on balance, one prefers (i.e. one believes in) this hypothesis over agnostic and religious alternatives. This means that scientists go into No Line? 419 combat with one hand tied behind their backs when arguing the merits of a case with a non-scientist who is not so encumbered. In Rushdie’s words [1]: One of the beauties of learning is that it admits its provisionality, its imperfections. This scholarly scrupulousness, this willingness to admit that even the most well supported of theories is still a theory, is now being exploited by the unscrupulous. But that we do not know everything does not mean that we know nothing. Given all this, can a scientist speak objectively about religion in general, and about creationism in particular? By now, scientists have a good track- record of providing examples where apparently objective human perceptions have been shown false. Early man probably considered the earth to be flat. Scientific observation of astronomical objects led to the realization that we – all six billion of us – are standing on the surface of an approximately spheri- cal earth. The hypothesis was proven by circumnavigation of the planet by early explorers. So, unless there is something we have overlooked, the surface of the earth taken as a whole (i.e. disregarding small segments) is not flat. More precisely, the probability that the planet’s surface is flat may be considered very low. Perhaps, likewise, scientists can show that some religious postulates may be insecure.

No Beginning? A fundamental observation that underlies much creationist thinking is that everything around us appears to have a beginning and an end. To create, after all, means making something begin. If there is no beginning there can be no creationism. I have sketched out here and in my previous books [5, 9] – with a degree of detail that I believe even the most recalcitrant of bickering evolutionists will be able to live with – a likely path from complex organic molecules to complex living organisms. Others have made the case for the derivation of complex organic molecules from inorganic precursor molecules. Let’s examine this further. The building up of inorganic molecules from even simpler units has been, and remains, an area of intense study based on the premise that there is some fundamental entity (“strings” in modern parlance) from which everything is constituted [10]. The important point is that there is a unified chain of relationships down from highly complex organisms to a fundamental substratum which, quite simply, exists. Thus, as a point of departure, most scientists accept the concept that there is something fundamental, of a relatively low order of complexity, that exists through all time. Their concern is to find what that fundamental is. They feel no need to invoke an abstract creator who might have made that fundamental. In short, scientists can accept something as being. Accordingly, there is no 420 Appendix 3 beginning or, necessarily, end, for that something. Thus, it is a law of thermodynamics that energy can be neither created nor destroyed. Energy, what ever it is, just is. Or, if it is destroyed, it converts into matter, whatever that is, according to Einstein’s famous equation. Energy and matter interconvert- ably exist. So scientists can accept the concept of being. They accept the concept of existing through time. But so can creationists. In their case the entity that is constant through time is the creator who, by “intelligent design,” has put it all together. Whereas the constant entity for the scientists is relatively simple, the constant entity for the creationists would appear to be, given its key at- tribute as creator, highly complex. The two curves (A and B) shown in Figure 23.1 indicate the roles of this entity, termed “God”, first to create the fundamental units out of which everything derives, and then, perhaps, to prescribe (influence) the path this derivation will take. The fact that the latter curve (B) is not obligatory for the God concept is overlooked by some scientists who hold that our ability to explain the path without resorting to a supernatural power destroys the concept [11, 12]. One scientist has embraced both simple and complex constant entities. Disregarding the writings of mathematicians and physicists on what may be the true nature of time (as, through ignorance, do I), the priest and anthropologist Pierre Teilhard de Chardin stood back from the phenomena before him, and saw just one process – matter becoming aware of itself [13]. This required time that would stretch endlessly backwards and forwards from the present, so that what we can conceive as happening, either has already hap- pened (if it is possible to happen at all), or is part of some recursive cycle, or seems intrinsically without end (like the number of decimal places in the ratio of the circumference of a circle to its radius). In Chardin’s view the process is ongoing and tends to produce forms and relationships of increasing complexity that can be extrapolated to an ultimate “omega point” where the degree of complexity would approach a maximum, tending to be constant in time. All this can be summarized as two boxes and an arrow (Fig. 23.1). The difference between Chardin’s omega point and the creationists’ God, is that the latter is often held capable of influencing the path from simple to complex (curved arrows), whereas the former does not. There is the possibility, doubtless explored in the science fiction literature, of a distant omega point having arisen independently of us, which would choose somehow to influence our evolutionary path, but Chardin does not counte- nance this. Chardin had to bide his time before the church would allow his works to be made public. Predictably, when they appeared they were attacked by the establishment of his day no less vigorously than those of Butler were attacked in his time. No Line? 421

Fig. 23.1. Two extremes of the complexity scale (boxed) that exist through time. Intermediate states appear ephemeral. The curved arrows indicate the possibilities of feedbacks either at the beginning (A) or during (B) the process of increasing complexity (the thick horizontal arrow).

Can Intermediate States Exist? Under the scheme shown in Figure 23.1, we six billion humans are located somewhere in space and time along the arrow leading from low to high complexity. The following question can now be asked: If the two extremes can, quite simply, exist, is it not possible that an intermediate state, such as that in which we currently find ourselves, could also, quite simply, exist, or, at least, have the potential to exist? To this, most of the six billion would answer with a resounding “no.” Everything that they see – including themselves, their friends, and their relatives – appears ephemeral, impermanent. Everything has a beginning and an end. However, many presumptively ephemeral, impermanent, things can be rendered less ephemeral, and perhaps permanent, if we so will it. For example, for millennia people have agreed to live together on the banks of the River Thames in a geographic region named London. Just as the individual molecules of water in the river are for ever changing, so are the people who make up London’s population. But London remains. Those who will this far outnumber, and/or so far have defeated, those who might will 422 Appendix 3 otherwise. So London has the potential to persist through time to constitute part of that which will exist at Chardin’s omega point. Similarly, through each person – indeed, through each organism on the planet – there is a constant flux of molecules. By recycling, replacement and repair (Chapter 2), today’s new molecules substitute for yesterday’s. We, as individuals – a collective of molecules – persist. And, hypothetically, there is no limit to the duration of this persistence, so that we also have the potential to constitute part of that which will exist at Chardin’s omega point. Thomas Huxley saw this in 1879 [14]: The animal mechanism is continually renewed and repaired; and though it is true that individual components of the body are constantly dying, yet their places are taken by vigorous successors. A city remains notwith- standing the constant death-rate of its inhabitants; and … an organism … is only a corporate unity, made up of innumerable partially independent individualities. He concluded: That all living beings sooner or later perish needs no demonstration, but it would be difficult to find satisfactory grounds for the belief that they needs must do so. The analogy of a machine, that sooner or later must be brought to a standstill by the wear and tear of its parts, does not hold. Cells taken from cats, dogs or humans thrive equally well when cultured away from the body, and can appear potentially immortal. Yet cats and dogs seldom live beyond twenty years – the time it takes humans to reach their physical prime. Our understanding of the biology of this is increasing (Chap- ter 17). To some scientists it does not seem unrealistic to suppose that, in centuries hence (some hyperoptimists/hyperpessimists – depending on how you view it – think sooner), humans, perhaps having opted finally to liberate themselves from religious mythology, will choose to ‘permanise’ themselves as entities that, quite simply, exist. Quoting from Benjamin Disraeli in Endymion, Butler considered it a matter of will [15]: “There is nothing like will; everybody can do exactly what they like in this world, provided they really like it.” If this is as true as I believe it to be, “the longing after immortality,” though not indeed much of an argument in favour of our being immortal at the present moment, is perfectly sound as a reason for concluding that we shall one day develop immortality, if our desire is deep enough and lasting enough. Biological knowledge is approaching a state such that all diseases could be either prevented or cured. Considering the process of biological aging as a disease, it also might be slowed, or even halted. This, in itself, would serve partly to dispel religious mythology, much of which seeks to ameliorate the fear of death. We can envisage a scenario such that, as perceptual dust and No Line? 423 cobwebs clear away, and births and deaths and the associated rituals become infrequent events, people will increasingly come to recognize the existential nature of their being. There will still be churches and priests. But the latter will bring comfort through truth, rather than through mythology. They will describe religions as relics of ancient ways of thinking, celebrate the present, and help people to look afresh at the two fundamental questions. Our evolution as biological entities will slow, giving way to the evolution of the information each generation holds in trust.

Contradiction Shall Reign! So, where will the priests (‘officients’) say we came from? It seems that we came from something fundamental, from which inorganic matter is composed, and which, quite simply, exists. How shall we conduct ourselves? Again, quite simply, in such ways as should further an agreeable existence. And we will bicker endlessly, without fear of recrimination, on all topics, including that of what constitutes an agreeable existence. In short, we will be free! In Rushdie’s words [1]: “Freedom is that space in which contradiction can reign, it is a never ending debate.” Or, as Samuel Butler put it a century earlier [15]: “Whenever we push truth hard she runs to earth in contradiction in terms, that is to say, in falsehood. An essential contradiction in terms meets us at the end of every enquiry.” We also will debate possible omega points towards which we might collec- tively strive, and some may come to agree with Thomas Huxley [16] that: The purpose of our being in existence, the highest object that human beings can set before themselves, is not the pursuit of some chimera as the annihilation of the unknown; but it is simply the unwearied endeavour to remove its boundaries a little further from our sphere of action. Butler of course said it more simply, and with his usual twist of humor [15]. If I thought by learning more and more I should ever arrive at the knowledge of absolute truth, I should leave off studying. But I believe I am pretty safe. In other words, we will strive to further the evolution of the sort of information that will help our understanding. How does all this accord with the three rules of thumb? Quite well with the first two. In not invoking elusive supernatural powers, one arrives at a scenario of moderate simplicity. And those who advocate this view, including those trained in science, while having much to gain intellectually from its wide acceptance, usually do not gain materially to such an extent as the ar- dent advocates of religious viewpoints. Thus, we should not be overly suspi- cious of the motives of those advocating the view (third rule of thumb). 424 Appendix 3

We should neither regard such individuals as shallow, nor impute an absence of sensitivity, or an innate inability to be moved at the wonder of it all. Atheists are no less sympathetic to the needs of others than the religiously inclined; nor are they moved less by great music, great art, the quiet splendor of a sunset, and the silver path to the moon at sea. The lives of Samuel Butler and William Bateson attest to this. The difference is that atheists consider the latter to be works of individual genius, or of natural forces, not of a God working through man or through Nature. When things go wrong they see that “the fault, dear Brutus, lies not in the stars, but in ourselves” [17]. But, as we saw in Chapter 19, perhaps there is no line between us and “the stars.”

Acknowledgements

I am indebted to Jim Gerlach and David Siderovski for much patient advice in the 1980s as I struggled to understand computers. My bioinformatic studies were enthusiastically assisted by a host of computer-literate students in the Department of Biochemistry at Queen’s University in Canada. Special thanks to Isabelle Barrette, Sheldon Bell, Labonny Biswas, Yiu Cheung Chow, Anthony Cristillo, Kha Dang, Previn Dutt, Scott Heximer, Gregory Hill, Janet Ho, Robin Lambros, Perry Lao, Justin LeBlanc, Shang-Jung Lee, Feng-Hsu Lin, Christopher Madill, James Mortimer, Robert Rasile, Jonathan Rayment, Scott Smith, Theresa St. Denis, and Hui Yi Xue. Insight into the differing perceptions of the ‘info’ people and the ‘bio’ people came in the 1990s when Janice Glasgow of the Department of Computing and Information Science at Queen’s University invited me to join her in initi- ating a graduate course in Bioinformatics, and Paul Young of the Department of Biology invited me to contribute to his undergraduate Genomics course. His text, Exploring Genomes, was published in 2002. Andrew Kropinski of the Department of Microbiology and Immunology advised on bacteriophage genomes. Peter Sibbald advised on bits and bytes. David Murray of the De- partment of Psychology provided valuable biohistorical information and, among many, the works of biohistorian William Provine (Cornell University) were of great help in my getting ‘up to speed’ in that area. Special thanks are due to Mary Catherine Bateson, and to Alan G. Cock (1926-2005) and his family, for facilitating access to historical materials relating to William Bateson. Charlotte Forsdyke copy-edited. Polly Forsdyke advised on German usages and translated the French and German versions of Delboeuf’s 1877 paper into English. Sara Forsdyke advised on Latin and Greek usages. Ruth Forsdyke believed in me, sometimes more than I did myself, and suggested the term “reprotype.” My wife Patricia is a constant source of inspiration and encouragement. Sheldon Bell, Christopher Madill and James Mortimer wrote programs that greatly facilitated our bioinformatic analyses. Michael Zuker of the 426 Acknowledgements

Rensselaer Polytechnic Institute kindly made available his nucleic acid folding programs. Dorothy Lang gave me information on mirror repeats prior to publication. The Genetics Computer Group (GCG) suite of programs (“the Wisconsin package”) acquiesced to modification by my primitive UNIX scripts. In recent years there have been a productive collaboration with Chiyu Zhang (Jiangsu University) and Ji-Fu Wei (Nanjing Medical University), and helpful correspondence with Michel E. B. Yamagishi (Cidade Universitária Zeferino Vaz - Barão Geraldo). For the first edition, Joseph Burns, Deborah Doherty and Marcia Kidston (Springer, Norwall) smoothed the passage from manuscript to final copy. Melanie Wilichinsky, Meredith Clinton and Andrea Macaluso (Springer, New York) did likewise for the second. Original data for figures were gener- ously provided by Kenneth Wolfe and Paul Sharp (Fig. 7.3), by Honghui Wan and John Wootton of the National Center for Biotechnology Informa- tion (Fig. 14.1), and by Daiya Takai and Peter Jones of the University of Southern California (Fig. 18.2). Most other data were publicly available from sources such as GenBank and the ExInt Database (Fig. 13.2). The photograph of Erwin Chargaff was from the collection of the National Library of Medi- cine, Washington. The photograph of Samuel Butler is from a self-portrait held by St. John’s College, Cambridge, with permission of the Master and Fellows. The photograph of Friedrich Miescher was from the University of Basel. The photograph of Gregory Bateson was from the Imogen Cunning- ham Trust, California. The photograph of George Romanes was from the Royal Society collection. The photograph of Richard Goldschmidt is from the personal papers that Alan G. Cock entrusted to me in 2004 (now in the Queen’s University Archives). The photograph of William Bateson and Raphael Weldon is from Alan’s personal copy of the William Bateson papers (now in the Queen’s University Archives). Figure 2.1 was kindly adapted by Richard Sinden of Texas A & M University from his book DNA Structure and Function. Elsevier Science gave permission to use this, and also Figure 5.5 from an article by Michael Zuker and his colleagues in Methods in Enzy- mology, and Figure 16.3 from Max Lauffer’s Entropy Driven Processes in Biology. Figure 2.5 is adapted from an article by Austin and Marianne Hughes with permission of the authors and Nature Publishing Group. Figures 12.2 and 12.3 are reproduced from PLOS One with the permission of Donal Hickey (Concordia University, Montreal), and Elizabeth Clare (University of Guelph) provided supporting data. Permissions to reproduce or adapt materials from my own works were provided by Springer (Figs. 4.2 to 4.4, 7.2, 8.2, 10.1, 10.3, 11.4, 12.12, 13.4, 13.5), Cold Spring Harbor Laboratory Press (Fig. 6.2), McGill-Queen’s Uni- versity Press (Figs. 8.1, 8.3, 8.4, 9.6 and 17.3), Elsevier Science (Tables, 10.1, 13.1; Figs. 5.3, 5.4, 5.7, 6.1, 6.7, 13.6, 13.7, 14.2, 14.4 to 14.7, 14.9, Acknowledgements 427

15.1 to 15.3, 16.5), Adis International Limited (Table 4.3; Figs. 12.1 and 12.4 to 12.10), Oxford University Press (Fig. 13.3), World Scientific Publishing Company (Figs. 11.3, 16.1 and 16.2), and the Royal Society (Figs. 19.3 to 19.5). For space reasons many important studies are not directly cited. How- ever, the studies that are cited often contain references to those studies. My web pages are hosted by Queen’s University (for internet locations see the beginning of the reference section of this book). These display full-texts of various scientific papers from the nineteenth century onwards, and much supplementary material. Here the reader will find regular updates on new work that appeared after the book went to press. To supplement this and my previous books, I have written short biographies of W. Bateson, E. Chargaff, J. B. S. Haldane, G. J. Mendel, H. J. Muller and G. J. Romanes. Nature Pub- lishing Group placed these in both on-line and paper editions of the Nature Encyclopedia of Life Sciences (2002) and/or the Nature Encyclopedia of the Human Genome (2003). In 2005 these became the Encyclopedia of Life Sci- ences, published by John Wiley & Sons, and available on-line at http://www.els.net/. I have also provided an overview of introns in Chapters 4 and 8 of Lewin’s GENES X (2010; Jones & Bartlett, Sudbury). Finally, there is a rather unusual acknowledgement of an anticipatory rather than retrospective nature. First, a quotation from Unconscious Memory concerning Samuel Butler’s attempts to make the Victorian evolutionists recognize both the ideas of Hering and himself, and their own intellectual debts to Georges Louis Leclerc de Buffon and Charles Darwin’s grandfather, Erasmus Darwin: My own belief is that people paid no attention to what I said, as believing it simply incredible, and that when they come to know that it is true, they will think as I do concerning it. … My indignation has been mainly roused … by the wrongs … inflicted on dead men, on whose behalf I now fight, as I trust that some one – whom I thank in anticipation – may one day fight on mine. The reader will recognize that, a century after his death, I have here fought on Butler’s behalf. I respectfully accept his thanks, while noting his caution To Critics and Others that the future might come to “see in me both more and less than I intended”. But the battle is not yet won. So, in turn, I thank in anticipation that some one who may, one day, continue our work.

References and Notes1

Prologue – To Select is Not To Preserve 1. Romano T (2002) Making Medicine Scientific. John Burdon Sanderson and the Culture of Victorian Science. John Hopkins University Press, Baltimore, p 105 [Sanderson was the great uncle of the twentieth century’s “JBS”, John Burdon Sanderson Haldane, and may have partly inspired Lydgate in George Eliot’s Middlemarch.] 2. Brenner S (2002) The tale of the human genome. Nature 416:793-794 3. Forsdyke DR (2001) Did Celera invent the Internet? The Lancet 357:1204 4. Wu X, Li Y, Crise B, Burgess SM (2003) Transcription start regions in the human genome are favored targets of MLV integration. Science 300:1749- 1751 5. Brenner S (1991) Summary and concluding remarks. In: Osawa S, Honjo T (eds) Evolution of Life: Fossils, Molecules and Culture. Springer-Verlag, Berlin, pp 453-456 6. Little P (1995) Navigational progress. Nature 277:286-287

1 Full text versions of some of these references, together with much supplementary information, may be found in my web-pages, which are regularly updated. The pages may be accessed at:

http://post.queensu.ca/~forsdyke/homepage.htm

Early versions of the latter web-pages are archived at:

http://www.archive.org https://qspace.library.queensu.ca/html/1974/421/homepage.htm

The date of a written work sometimes does not coincide with that of its publication. When this problem arises I give the date of the written work after the author’s name, and the date of publication with the publisher’s name. 430 References and Notes

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Chapter 3 – Information Levels and Barriers 1. Bateson G (1967) Cybernetic explanations. American Behavioural Scientist 10:29-32 2. Romanes GJ (1891) Aristotle as a naturalist. Contemporary Review 59:275- 289 3. Delbrück M (1971) Aristotle-totle-totle. In: Monod J. Borek F (eds) Of Mi- crobes and Life. Columbia University Press, New York, pp 50-55 4. Lyell C (1863) The Geological Evidences of the Antiquity of Man with Re- marks on Theories of the Origin of Species by Variation. Childs, Philadel- phia, p 467 5. Shaw GB (1913) Pygmalion. In: Bernard Shaw. Complete Plays with Pref- aces. Volume I. Dodd, Mead, New York (1963) 6. Galton F (1876) A theory of heredity. Journal of the Anthropological Insti- tute 5:329-348 7. Butler S (1923) Life and Habit. Trübner, London, pp 172-180, 200-201 [“Locus poenitentiae” is Latin for a “place of repentance.” Legally the term signifies a, perhaps brief, temporal safe-haven where there is an opportunity to change one’s mind. Thus, between the last bid and the fall of the auction- eer’s hammer there is a locus poenitentiae for a decision, which cannot be stretched out for ever. Technically, a cross between a male horse and a female donkey results in a “hinny,” whereas a cross between a female horse and a male donkey results in a “mule.” Butler did not bother with such niceties, claiming that “I neither know, nor want to know, more detail than is necessary to enable me to give a fairly broad and comprehensive view of my subject.”] 8. Olby R, Posner E (1967) An early reference on genetic coding. Nature 215:556 9. Du Maurier D (1952) The Birds. Penguin Books, London. 10. Jenkin F (1867) The origin of species. The North British Review 46:277-318 436 References and Notes

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Chapter 4 – Chargaff’s Second Parity Rule 1. Dickens C (1837) The Posthumous Papers of the Pickwick Club. Chapman- Hall, London 2. Moliere (1670) Le Bourgeous Gentilhomme. Oliver TE (ed) Ginn, New York (1914) 3. Bök C (2001) Eunoia. Coach House Books, Toronto 4. Perec G (1972) Les Revenentes. Julliard, Paris 5. Perec G (1969) La Disparition. Denoël, Paris 6. Ohno S (1991) The grammatical rule of DNA language: messages in palin- dromic verses. In: Osawa S, Honjo T (eds) Evolution of Life. Springer- Verlag, Berlin, pp 97-108 7. Rudner R, Karkas JD, Chargaff E (1968) Separation of B. subtilis DNA into complementary strands. III. Direct analysis. Proceedings of the National Academy of Sciences USA 60:921-922 8. Bell SJ, Forsdyke DR (1999) Accounting units in DNA. Journal of Theo- retical Biology 197:51-61 Prologue – To Select is Not To Preserve 437

9. Darwin C (1871) The Descent of Man and Selection in Relation to Sex. John Murray, London, p 316 10. Edwards AWF (1998) Natural selection and the sex ratio. American Natu- ralist 151:564-569 11. Forsdyke DR (2002) Symmetry observations in long nucleotide sequences. Bioinformatics 18:215-217 12. Prabhu VV (1993) Symmetry observations in long nucleotide sequences. Nucleic Acids Research 21:2797-2800 13. Forsdyke DR (1995) Relative roles of primary sequence and (G+C)% in determining the hierarchy of frequencies of complementary trinucleotide pairs in DNAs of different species. Journal of Molecular Evolution 41:573-581 14. Josse J, Kaiser AD, Kornberg A (1961) Enzymatic Synthesis of Deoxyribo- nucleic Acid. VIII. Frequencies of nearest neighbor base sequences in deoxyribonucleic acid. Journal of Biological Chemistry 236:864-875 15. Russell GJ, Walker PMB, Elton RA, Subak-Sharpe JH (1976) Doublet frequency analysis of fractionated vertebrate DNA. Journal of Molecular Biol- ogy 108:1-23 16. Blaisdell BE (1986) A measure of the similarity of sets of sequences not re- quiring sequence alignment. Proceedings of the National Academy of Sci- ences USA 83:5155-5159 17. Rogerson AC (1989) A sequence asymmetry of the Escherichia coli chromosome appears to be independent of strand or function and may be evolutionarily conserved. Nucleic Acids Research 17:5547-5563 18. Rogerson AC (1991) There appear to be conserved constraints on the distribution of nucleotide sequences in cellular genomes. Journal of Molecular Evolution 32:24-30 19. Yomo T, Ohno S (1989) Concordant evolution of coding and noncoding regions of DNA made possible by the universal rule of TA/CG deficiency – TG/CA excess. Proceedings of the National Academy of Sciences USA 86:8452-8456 20. Bultrini E, Pizzi E, Guidice P Del, Frontali C (2003) Pentamer vocabularies characterizing introns and intron-like intergenic tracts from Caenorhabditis elegans and Drosophila melanogaster. Gene 304:183-192 21. Lobry JR, Sueoka N (2002) Asymmetric directional mutation pressures in bacteria. Genome Biology 3 (10):research 0058. 22. Forsdyke DR, Bell SJ (2004) Purine-loading, stem-loops, and Chargaff’s second parity rule: a discussion of the application of elementary principles to early chemical observations. Applied Bioinformatics 3:3-8 438 References and Notes

23. Baisnée P-F, Hampson S, Baldi P (2002) Why are complementary strands symmetric? Bioinformatics 18:1021-1033 24. Sueoka N (1995) Intrastrand parity rules of DNA base composition and usage biases of synonymous codons. Journal of Molecular Evolution 40:318- 325 25. Phillips GJ, Arnold J, Ivarie R (1987) The effect of codon usage on the oligonucleotide composition of the E. coli genome and identification of over- and underrepresented sequences by Markov chain analysis. Nucleic Acids Research 15:2627-2638 26. Nussinov R (1981) Eukaryotic dinucleotide preference rules and their implications for degenerate codon usage. Journal of Molecular Biology 149:125- 131 27. Forsdyke DR, Zhang C, Wu J-F (2010) Chromosomes as interdependent accounting units. The assigned orientation of C. elegans chromosomes minimizes the total W-base Chargaff difference. Journal of Biological Systems 18:1-16

Chapter 5 – Stems and Loops 1. Crick F (1974) Letter to H. G. Khorana, 28th June. Archives of National Li- brary of Medicine, Washington, DC 2. Delbrück M (1949) Transactions of the Connecticut Academy of Arts and Sciences 38: 173-190 3. Salser W (1970) Discussion. Cold Spring Harbor Symposium in Quantita- tive Biology 35: 19 4. Ball LA (1972) Implications of secondary structure in messenger RNA. Journal of Theoretical Biology 36:313-320 5. White HB, Laux BE, Dennis D (1972) Messenger RNA structure: compatibility of hairpin loops with protein sequence. Science 175:1264-1266 6. Forsdyke DR (1998) An alternative way of thinking about stem-loops in DNA. Journal of Theoretical Biology 192:489-504 7. Seffens W, Digby D (1999) mRNAs have greater negative folding free energies than shuffled or codon choice randomized sequences. Nucleic Acids Research 27:1578-1584 8. Forsdyke DR (2007) Calculation of folding energies of single-stranded nucleic acid sequences: conceptual issues. Journal of Theoretical Biology 248:745-753 9. Tinoco I, Uhlenbeck OC, Levine MD (1971) Estimating secondary structure in ribonucleic acids. Nature 230:362-367 Prologue – To Select is Not To Preserve 439

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Chapter 6 – Chargaff’s Cluster Rule 1. Chargaff E (1963) Essays on Nucleic Acids. Elsevier, Amsterdam, pp 124, 148 2. Szybalski W, Kubinski H, Sheldrick P (1966) Pyrimidine clusters on the transcribing strands of DNA and their possible role in the initiation of RNA 440 References and Notes

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17. Necsulea A, Guillet C, Cadoret J-C, Prioleau M-N, Duret L (2009) The relationship between DNA replication and human genome organization. Mo- lecular Biology & Evolution 26:729-741 18. Chargaff E (1951) Structure and function of nucleic acids as cell constituents. Federation Proceedings 10:654-659 19. Elson D, Chargaff E (1955) Evidence of common regularities in the composition of pentose nucleic acids. Biochemica Biophysica Acta 17:367-376 20. Wang H-C, Hickey DA (2002) Evidence for strong selective constraints acting on the nucleotide composition of 16S ribosomal RNA genes. Nucleic Acids Research 30:2501-2507 21. Forsdyke DR, Bell SJ (2004) Purine-loading, stem-loops, and Chargaff’s second parity rule: a discussion of the application of elementary principles to early chemical observations. Applied Bioinformatics 3:3-8 22. Eguchi Y, Itoh T, Tomizawa J (1991) Antisense RNA. Annual Reviews of Biochemistry 60:631-652 23. Brunel C, Marquet R, Romby P, Ehresmann C (2002) RNA loop-loop interactions as dynamic functional motifs. Biochimie 84:925-944 24. Cristillo AD, Heximer SP, Forsdyke DR (1996) A ‘stealth’ approach to inhibition of lymphocyte activation by oligonucleotides complementary to the putative G0/G1 switch regulatory gene G0S30/EGR1/ZFP6. DNA and Cell Biology 15:561-570 25. Paz A, Mester D, Baca I, Nevo E, Korol A (2004) Adaptive role of increased frequency of polypurine tracts in mRNA sequences of thermophilic prokaryotes. Proceedings of the National Academy of Sciences USA 101:2951-2956 26. Spees JL, Olson SD, Whitney MJ, Prockop DJ (2006) Mitochondrial transfer between cells can rescue aerobic respiration. Proceedings of the Na- tional Academy of Sciences USA 103:1283-1288 27. Mitra K, Roysam B, Lin G, Lippincott-Schwartz J (2009) A hyperfused mitochondrial state achieved at G1–S regulates cyclin E buildup and entry into S phase. Proceedings of the National Academy of Sciences USA 106:11960-11965 28. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, Chan DC (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280-289 29. Louis EJ (2009) Origins of reproductive isolation. Nature 457:549-550

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Chapter 7 – Mutation 1. Bateson W (1894) Materials for the Study of Variation Treated with Espe- cial Regard for Discontinuity in the Origin of Species. Macmillan, London, pp 6, 85, 573 2. Bossi L, Roth JR (1980) The influence of codon context on genetic code translation. Nature 286:123-127 3. Simonson AB, Lake JA (2002) The transorientation hypothesis for codon recognition during protein synthesis. Nature 416:281-285 4. Eigen M, Schuster P (1978) The hypercycle. A principle of natural self- organization. Part C. The realistic hypercycle. Naturwissenschaften 65:341- 369 5. Shepherd JCW (1981) Method to determine the reading frame of a protein from the purine/pyrimidine genome sequence and its possible evolutionary justification. Proceedings of the National Academy of Sciences USA 78:1596-1600 6. Forsdyke DR (2006) Positive Darwinian selection. Does the comparative method rule? Journal of Biological Systems 15, 95-108 7. Forsdyke DR (2002) Selective pressures that decrease synonymous mutations in Plasmodium falciparum. Trends in Parasitology 18:411-418 8. Wolf JBW, Künstner A, Nam K, Jakobsson M, Ellegren H (2009) Nonlinear dynamics of nonsynonymous (dN) and synonymous (dS) substitution rates affects inference of selection. Genome Biology & Evolution 2009: 308-319 9. Fitch WM (1974) The large extent of putative secondary nucleic acid structure in random nucleotide sequences or amino acid-derived messenger- RNA. Journal of Molecular Evolution 3:279-291 10. Bernardi G, Bernardi G (1986) Compositional constraints and genome evolution. Journal of Molecular Evolution 24:1-11 11. Wolfe KH, Sharp PM (1993) Mammalian gene evolution: nucleotide sequence divergence between mouse and rat. Journal of Molecular Evolution 37:441-456 12. Novella IA, Zarate S, Metzgar D, Ebendick-Corpus, BE (2004) Positive selection of synonymous mutations in vesicular stomatitis virus. Journal of Molecular Biology 342:1415–1421 13. Bains W (1987) Codon distribution in vertebrate genes may be used to predict gene length. Journal of Molecular Biology 197:379-388 [A study of “coincident codons”.] 14. Sempath R et al. (2007) Global surveillance of emerging influenza virus genotypes by mass spectrometry. PLOS One: 2, issue 5, e489 Prologue – To Select is Not To Preserve 443

15. Blaisdell BE (1986) A measure of the similarity of sets of sequences not re- quiring sequence alignment. Proceedings of the National Academy of Sci- ences USA 83:5155-5159 16. Bronson EC, Anderson JN (1994) Nucleotide composition as a driving force in the evolution of retroviruses. Journal of Molecular Evolution 38:506-532 17. Qi J, Wang B, Hao BL (2004) Whole proteome prokaryote phylogeny without sequence alignment: a K-string composition approach. Journal of Mo- lecular Evolution 58:1-11 18. Richter M, Rosselló-Móra R (2009) Shifting the genomic gold standard for the prokaryotic species definition. Proceedings of the National Academy of Sciences USA 106:19126-19131. 19. Yang K, Zhang L (2008) Performance comparison between k-tuple distance and four model-based distances in phylogenetic tree reconstruction. Nucleic Acids Res. 36 (5):e33 20. Venditti C, Pagel M (2009) Speciation as an active force in promoting genetic evolution. Trends in Ecology & Evolution 25:14-20 21. Venditti C, Meade A, Pagel M (2010) Phylogenies reveal new interpretation of speciation and the Red Queen. Nature 463:349-352 22. Darwin C (1856) Letter to J. D. Hooker. In: Darwin F (ed) Life and Letters of Charles Darwin. Volume 1. Appleton, New York (1887) p 445 23. Forsdyke DR (2001) The Origin of Species, Revisited. A Victorian who An- ticpated Modern Developments in Darwin’s Theory. McGill-Queen’s Uni- versity Press, Montreal 24. Darwin C (1872) On the Origin of Species by Means of Natural Selection. 6th Edition. John Murray, London, Introduction [By the 6th edition, Darwin was more inclined to the view that some acquired characters might be inher- ited (Lamarckism). This is perhaps why he then questioned the sufficiency of natural selection as an explanation for evolutionary advance.] 25. Chargaff E (1963) Essays on Nucleic Acids. Elsevier, Amsterdam, p 95

Chapter 8 – Species Survival and Arrival 1. Bennett JH (1983) Natural Selection, Heredity and Eugenics. Including Se- lected Correspondence of R. A. Fisher with Leonard Darwin and Others. Clarendon Press, Oxford, p 122 2. Butler S (1862) Darwin and the origin of species. Reproduced from The Press of Christchurch. In: Streatfeild RA (ed) The First Year in Canterbury Settlement with Other Early Essays. Fifield, London, (1914) pp 149-164 3. Fisher RL (1930) The Genetical Theory of Natural Selection. Oxford Uni- versity Press, Oxford 444 References and Notes

4. Darwin C (1856) Letter to J. D. Hooker. In: Darwin F (ed) Life and Letters of Charles Darwin. Volume 1. Appleton, New York (1887) p 445 5. Bateson W (1909) Heredity and variation in modern lights. In: Seward AC (ed) Darwin and Modern Science. Cambridge University Press, Cambridge pp 85–101 6. Darwin C (1857) Letter to T. H. Huxley. In: Darwin F (ed) More Letters of Charles Darwin, Vol 1. Appleton, New York (1903) p 102 7. Hooker J (1860) On the origination and distribution of species. Introductory essay on the flora of Tasmania. American Journal of Science & Arts 29:1- 25, 305-326 8. Mendel G (1865) Versuche uber Pflanzen Hybriden. Verhandlung des naturforschenden Vereines in Brunn 4:3–47 [The pea plant was a happy choice for Mendel. In this species the height character can be treated as unigenic. He was less fortunate in his studies with other plants.] 9. Romanes GJ (1894) Letter to Schafer, 18th May. Wellcome Museum of the History of Medicine, London [Romanes cited Mendel in an article on “Hy- bridism” in the Encyclopaedia Britannica, 1881.] 10. Darwin C (1866) Letter to A. R. Wallace. In: Marchant J (1916) Alfred Rus- sel Wallace. Letters and Reminiscences. Harper, New York 11. Butler S (1878) Life and Habit, Trübner & Co., London, p. 168 12. Bateson W (1894) Materials for the Study of Variation Treated with Espe- cial Regard for Discontinuity in the Origin of Species. Macmillan, London, pp 85, 573 13. Bateson W, Saunders ER (1902) Report 1. Reports to the Evolution Com- mittee of the Royal Society. Harrison, London 14. Lind PA, Tobin C, Berg OG, Kurland CG, Andersson DI (2010) Compensa- tory gene amplification restores fitness after inter-species gene replace- ments. Molecular Microbiology 75:1078-1089 15. Forsdyke DR (2001) The Origin of Species, Revisited. A Victorian Who An- ticipated Modern Developments in Darwin’s Theory. McGill-Queen’s Uni- versity Press, Montreal 16. Crichton M (1990) Jurassic Park. Knopf, New York 17. Coyne JA, Orr HA (2004) Speciation. Sinauer, Sunderland, MA 18. Schartl M (2008) Evolution of Xmrk: an oncogene, but also a speciation gene? BioEssays 30:822-832 19. Richmond ML, Dietrich MR (2002) Richard Goldschmidt and the crossing- over controversy. Genetics 161:477-482 Prologue – To Select is Not To Preserve 445

20. Goldschmidt R (1940) The Material Basis of Evolution. Yale University Press, New Haven, pp 205-6, 245-248 [The term “reaction system” was introduced to distinguish large genetic units, between which recombination was restricted (i.e. each was an individual “reaction system”), from individual genes that exhibited standard Mendelian behavior; see Goodspeed TH, Clausen RE (1917) American Naturalist 51:31-46, 92-101.] 21. Avery OT, Macloed CM, McCarty M (1944) Studies on the chemical trans- formation of pneumococcal types. Journal of Experimental Medicine 79:137-158

Chapter 9 – The Weak Point 1. Butler S (1890) The deadlock in Darwinism. Universal Review. Reprinted in: Essays on Life, Art and Science, Streatfeild R (ed) Grant Richards, Lon- don, 1904, pp 234-340 2. Forsdyke DR (2010) George Romanes, William Bateson, and Darwin’s “weak point.” Notes & Records of the Royal Society 64:139-154 3. Bungener P, Buscaglia M (2003) Early connection between cytology and Mendelism: Micheal F. Guyer’s contribution. History and Philosophy in the Life Sciences 25: 27-50 4. Bateson W (1909) Heredity and variation in modern lights. In: Seward AC (ed), Darwin and Modern Science. Cambridge University Press, Cam- bridge, pp 85-101 5. Winge Ö (1917) The chromosomes. Their numbers and general importance. Comptes Rendus des Travaux du Laboratoire Carlsberg 13:131-275 6. Chandley AC, Jones RC, Dott HM, Allen WR, Short RV (1974) Meiosis in interspecific equine hybrids. 1. The male mule (Equus asinus X E. caballus) and hinny (E. caballus X E. asinus). Cytogenetics and Cell Genet- ics 13: 330-341 7. Greig D (2009) Reproductive isolation in Saccharomyces, Heredity 102, 39-44 8. Darwin C (1872) On the Origin of Species by Means of Natural Selection. 6th Edition. John Murray, London, Introduction

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454 References and Notes

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Chapter 16 – The Crowded Cytosol 1. Kipling R (1891) If. In: Rudyard Kipling’s Verse. Inclusive Edition 1885– 1918. Copp Clark, Toronto (1919) pp 645 2. Fulton AB (1982) How crowded is the cytoplasm? Cell 30:345-347 3. Wainwight M (2003) Early history of microbiology. Advances in Applied Microbiology 52:333-355 4. Forsdyke DR (1995) Entropy-driven protein self-aggregation as the basis for self/not-self discrimination in the crowded cytosol. Journal of Biological Systems 3:273-287 5. Lauffer MA (1975) Entropy-driven Processes in Biology. Springer-Verlag, New York [In addition to entropy, “volume exclusion” may play a role in crowding phenomena; see Minton AP (2001) The influence of macromolecular crowding and macromolecular confinement on biochemical reactions in physiological media. Journal of Biological Chemistry 276:10577- 10580.] 6. Forsdyke DR (2001) Adaptive value of polymorphism in intracellular self/not-self discrimination. Journal of Theoretical Biology 210:425-434 [Other collective protein functions include redox buffering and control of ionic equilibrium across membranes (Donnan equilibrium).] 7. Moreau-Aubry A, Le Guiner S, Labarrière N, Gesnel M-C, Jotereau F, Breathnach R (2000) A processed pseudogene codes for a new antigen recognized by a CD8+ T cell clone on melanoma. Journal of Experimental Medicine 191:1617-1623 Prologue – To Select is Not To Preserve 459

8. Goldschmidt R (1940) The Material Basis of Evolution. Yale University Press, New Haven, pp 266-271 9. Hickman HD, et al. (2003) Class 1 presentation of host peptides following human immunodeficiency virus infection. Journal of Immunology 171:22- 26 10. Darnell RB (1996) Onconeural antigens and the paraneoplastic neurological disorders: at the intersection of cancer, immunity and the brain. Proceedings of the National Academy of Sciences USA 93:4529-4536 11. Pardoll D (2002) T cells take aim at cancer. Proceedings of the National Academy of Sciences USA 99:15840-15842 12. Lane C, Leitch J, Tan X, Hadjati J, Bramson JL, Wan Y (2004) Vaccina- tion-induced autoimmune vitiligo is a consequence of secondary trauma to the skin. Cancer Research 64:1509-1514 13. Villasenor J, Besse W, Benoist C, Mathis D (2008) Ectopic expression of peripheral-tissue antigens in the thymic epithelium: probabilistic, monoalle- lic, misinitiated. Proceedings of the National Academy of Sciences USA 105:15854-15859 [T cells must run the MEC ‘gauntlet’ before release from the thymus.] 14. Murata S, Takahama Y, Tanaka K (2008) Thymoproteosome: probable role in generating positively selected peptides. Current Opinion in Immunology 20:192-196 15. Heaman EA (2003) St. Mary’s. The History of a London Teaching Hospital. McGill-Queen’s University Press, Montreal, p 322 16. Shull GH (1909) The “presence and absence” hypothesis. American Natu- ralist 43:410-419 17. Forsdyke DR (1994) The heat-shock response and the molecular basis of genetic dominance. Journal of Theoretical Biology 167:1-5 18. Rajan RS, Illing ME, Bence NF, Kopito RR (2001) Specificity in intracellular protein aggregation and inclusion body formation. Proceedings of the National Academy of Sciences USA 98:13060-13065 19. Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI (2006) Pro- gressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311:1471-1474 20. Wang L, Maji SK, Sawaya MR, Eisenberg D, and Roland Riek R (2008) Bacterial inclusion bodies contain amyloid-like structure. PLOS Biology 6: e195 21. Sangster TA, Lindquist S, Queitsch C (2004) Under cover: causes, effects and implications of Hsp90-mediated genetic capacitance. BioEssays 26:348- 362 460 References and Notes

22. Zinkernagel RM, Doherty PC (1974) Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semial- logeneic system. Nature 248:701-702 23. Forsdyke DR (1975) Further implication of a theory of immunity. Journal of Theoretical Biology 52:187-198 [This “affinity/avidity” model for positive repertoire selection is now generally accepted. An association between MHC proteins and antigens was implied, but it was a decade before the fine tailoring of antigens to create pMHC complexes came to light.] 24. Forsdyke DR (1991) Early evolution of MHC polymorphism. Journal of Theoretical Biology 150:451-456 25. Forsdyke DR (2005) “Altered-self” or “near-self” in the positive selection of lymphocyte repertoires. Immunology Letters 100:103-106

Chapter 17 – Rebooting the Genome 1. Naveira HF, Maside XR (1998) The genetics of hybrid male sterility in Drosophila. In: Howard DJ, Berlocher SH (eds) Endless Forms and Speci- ation. Oxford University Press, Oxford, pp 329-338 2. Delboeuf J (1877) Les mathématiques et le transformisme. Une loi mathé- matique applicable a la théorie du transformisme. La Revue Scientifique 29:669-679 3. Bernstein C, Bernstein H (1991) Aging, Sex and DNA Repair. Academic Press, San Diego, CA 4. Ridley M (2000) Mendel’s Demon. Gene Justice and the Complexity of Life. Orion Books, London, pp 167-201 5. Medvinsky A, Smith A (2003) Fusion brings down barriers. Nature 422:823-825 6. Reese V (2002) Mutation repair: a proposed mechanism that would enable complex genomes to better resist mutational entropy and which suggests a novel function for meiosis. The Human Behavior and Evolution Society 14th Annual Meeting, Rutgers University. Abstracts of presentations to session on "New Developments in Biology," June 21, p. 40 7. Butler S (1914) The Humour of Homer and Other Essays. Kennerley, New York, pp 209-313 8. Noort V van, Worning P, Ussery DW, Rosche WA, Sinden RR (2003) Strand misalignments lead to quasipalindrome correction. Trends in Genet- ics 19:365-369 9. Lolle SJ, Victor JL, Young JM, Pruitt RE (2005) Genome-wide non- Mendelian inherence of extra-genomic information in Arabidopsis. Nature 434:505-509 Prologue – To Select is Not To Preserve 461

10. Forsdyke DR (2001) The Origin of Species, Revisited. A Victorian Who Anticipated Modern Developments in Darwin’s Theory. McGill-Queen’s University Press, Montreal 11. Darwin C (1871) Descent of Man, and Selection in Relation to Sex. Apple- ton, New York, pp 245-311 12. Haldane JBS (1922) Sex ratio and unidirectional sterility in hybrid animals. Journal of Genetics 12:101-109 13. Coyne JA (1992) Genetics and speciation. Nature 355:511-515 14. Forsdyke DR (1995) Fine tuning of intracellular protein concentrations, a collective protein function involved in aneuploid lethality, sex- determination and speciation. Journal of Theoretical Biology 172:335-345 15. Chandley AC, Jones RC, Dott HM, Allen WR, Short RV (1974) Meiosis in interspecific equine hybrids. 1. The male mule (Equus asinus X E. caballus) and hinny (E. caballus X E. asinus). Cytogenetics & Cell Genetics 13:330-341 16. Vries H de (1889) Intracellular Pangenesis. Open Court, Chicago, (1910) pp 18-19 17. Darwin C (1851) A Monograph on the Subclass Cirripedia, vol. 1. The Ray Society, London, pp 281-293 18. Bateson W (1922) Evolutionary faith and modern doubts. Science 55:55-61 19. Goldschmidt R (1940) The Material Basis of Evolution, Yale University Press, New Haven, pp 233-236 20. Forsdyke DR (2000) Haldane's rule: hybrid sterility affects the heterogametic sex first because sexual differentiation is on the path to species differentiation. Journal of Theoretical Biology 204:443-452 21. Romanes GJ (1886) Physiological selection: an additional suggestion on the origin of species. Journal of the Linnean Society (Zoology) 19:337-411 22. Romanes GJ (1897) Darwin, and After Darwin: 3. Isolation and Physio- logical Selection. Longmans Green, London 23. Koller PC, Darlington CD (1934) The genetical and mechanical properties of the sex chromosomes. 1. Rattus norvegicus. Journal of Genetics 29:159- 173 24. Montoya-Burgos JI, Boursot P, Galtier N (2003) Recombination explains isochores in mammalian genomes. Trends in Genetics 19:128-130 25. Willard HF (2003) Tales of the Y chromosome. Nature 423:810-813 26. Warburton PE, Giordano J, Cheung F, Gelfand Y, Benson G (2004) In- verted repeat structure of the human genome: the X chromosome contains 462 References and Notes

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Chapter 18 – The Fifth Letter 1. Vinogradov AE (2005) Dualism of gene GC content and CpG pattern in regard to expression in the human genome: magnitude versus breadth. Trends in Genetics 21:633-639 2. Johnson TB, Coghill RD (1925) The discovery of 5-methyl-cytosine in tu- berculinic acid, the nucleic acid of the tubercle bacillus. Journal of the American Chemical Society 47: 2838-2844 3. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes & Development 16:6-21 4. Galagan JE, Selker EU (2004) RIP: the evolutionary cost of genome defence. Trends in Genetics 20:417-423 5. Semenov DA (2009) From the Wobble to Reliable Hypothesis. arXiv:0910.5371v1. [G-T pairing in DNA is likely to be weaker than G-U pairing in RNA because, when U is methylated (to become T) it inclines to the “keto,” rather than the “enol,” configuration and hydrogen bonding is weaker.] 6. Kusakabe, M. et al. (2009) Impact of DNA demethylation of the G0S2 gene on the transcription of G0S2 in squamous lung cancer cell lines with or Prologue – To Select is Not To Preserve 463

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20. Catherine M. Suter CM, David I.K. Martin DIK (2010) Paramutation: the tip of an epigenetic iceberg? Trends in Genetics 26:9-14 21. Pembrey ME, et al. (2006) Sex-specific, male-line transgenerational responses in humans. European Journal of Human Genetics 14:159-166 22. Butler S (1926) In: The Shrewbury Edition of the Works of Samuel Butler. Jones HF, Bartholomew AT (eds) Cape, London, volume 20, p.13 23. Gould SJ (1993) Fulfilling the spandrels of world and mind. In: Understanding Scientific Prose. Selzer J (ed) University of Wisconsin Press, Madison, WI, pp 310-336 24. Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nature Reviews Genetics 10:295-304 25. Molnar A, Melnyk CW, Bassett A, Hardcastle TJ, Dunn R, Baulcombe DC (2010) Small silencing RNAs in plants are mobile and direct epigenetic modification in recipient cells. Science 328:872-875 26. Netzer N, et al. (2009) Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 426:522-526

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Epilogue – To Preserve in Not To Select 1. Eliot G (1876) Daniel Deronda. William Blackman, London; (1879) Im- pressions of Theophrastus Such. Blackwood, Edinburgh [These were Eliot’s last books. She worked on Theophrastus Such from June to November 1878 and corrected proofs in March 1879 when Butler was writing the preface of Evolution, Old and New. Eliot’s partner, George Lewes, played a major role in establishing the Physiological Society. Romanes, who was Secretary to the Physiological Society and attacked Butler, was one of those privileged to attend Eliot’s ‘court’ at The Priory on Sunday afternoons. Butler probably served as her model for one of the friends of Theophrastus who antagonized Grampus (Darwin), and spoke of humans being superseded by machines (Chapter 1), which is the theme of her chapter entitled “Shadows of the Coming Race.”] 2. Chargaff E (1978) Heraclitean Fire. Sketches from a Life before Nature. Warner Books, New York [After being prematurely ‘retired,’ Chargaff ob- tained some laboratory space at the Roosevelt Hospital, New York, until 1992.] 468 References and Notes

3. Forsdyke DR (2000) Tomorrow’s Cures Today? Harwood Academic, Am- sterdam 4. Wilszek F, Devine B (1987) Longing for the Harmonies. Norton, New York, pp 111, 209 5. Kant I (1781) The Critique of Pure Reason. Guyer P, Wood AW (eds) Cambridge University Press, Cambridge (1998) 6. Haldane JS (1891) Letter to Louisa Trotter. 3 December. In: Romano T (2002) Making Medicine Scientific. John Burdon Sanderson and the Culture of Victorian Science. John Hopkins University Press, Baltimore (2002), p. 128 [JS Haldane’s son, JBS Haldane, was named after his great uncle.] 7. Darwin C (1868) Letter to Alfred Wallace. 27 February. In: Darwin F, Sew- ard AC (eds) More Letters of Charles Darwin. John Murray, London (1903), p 301 8. Olby RC (1966) Origins of Mendelism. Schocken Books, New York [The Victorians may have been unaware of Mendel, but in an article in Nature (1876) E. R. Lankester drew their attention to the work of Ewald Hering.] 9. Dawkins R (1983) Universal Darwinism. In: Bendall DS (ed) Evolution from Molecules to Man. Cambridge University Press, Cambridge, pp 403- 425 10. Forsdyke DR (2001) The Origin of Species, Revisited. A Victorian who An- ticipated Modern Developments in Darwin’s Theory. McGill-Queen’s Uni- versity Press, Montreal 11. Cock AG, Forsdyke DR (2008) “Treasure Your Exceptions.” The Science and Life of William Bateson. Springer, New York 12. Gould SJ (1982) The uses of heresy. Forward to reprint of: Goldschmidt R (1940) The Material Basis of Evolution. Yale University Press, New Haven, pp xiii-xlii 13. Gould SJ (1980) Is a new and general theory of evolution emerging? Paleo- biology 6:119-130 14. Gould SJ (2002) The Structure of Evolutionary Thought. Harvard Univer- sity Press, Cambridge, MA, pp 1002-1003 15. Forsdyke DR (2004) Grant Allen, George Romanes, Stephen Jay Gould and the evolution establishments of their times. Historic Kingston 52:94-98 16. Schwartz JS (2010) Darwin’s Disciple, George John Romanes. A Life in Letters. Lightning Rod Press, Diane Publishing Company, Darby, PA 17. Smith, JM (1995) Genes, memes and minds. The New York Review of Books 42: no. 19, pp 17-19 [The terms “ultra-Darwinian” and “neo-Darwinian” were used by Romanes to disparage Wallace’s and Weismann’s inflexible advocacy of the power of natural selection.] Prologue – To Select is Not To Preserve 469

18. Tooby J, Cosmides L (1997) [A letter to the editor of The New York Review of Books that was not accepted for publication: see http://cogweb.ucla.edu/ Debate/] 19. Adams MB (1990) La génétique des populations était-elle une génétique évolutive? In: Fischer J-L, Schneider WH (eds) Histoire de la Génétique, pp 153-171. ARPEM, Paris [See also: Adams MB. Little evolution, big evolution. Rethinking the history of population genetics. (unpublished personal communication, 2003)] 20. Provine WB (1992) Progress in evolution and the meaning of life. In: Wa- ters CK, Helden A van (eds) Julian Huxley, Biologist and Statesman of Sci- ence. Rice University Press, Houston, pp 165-180 21. Bateson P (2002) William Bateson: a biologist ahead of his time. Journal of Genetics 81:49-58 22. Butler S (1914) The Humour of Homer and Other Essays. Kennerley, New York, pp 245-313 23. Galison P (2003) Einstein’s Clocks, Poincaré’s Maps: Empires of Time. Norton, New York 24. Butler S (1985) The Notebooks of Samuel Butler. Jones HF (ed) Hogarth Press, London, pp 360-378 25. Shaw GB (1936) Samuel Butler. Introductory Essay. In: Butler S, The Way of All Flesh, Oxford University Press, London, pp v-xiii [Shaw added that “Butler and his clique belittled Grant Allen, one of the most amiably helpful men that ever lived, and one, moreover, who recognized Butler as a man of genius.” In turn, Butler heaped “scorn on Allen because he was not at once ready to declare that Butler was right about evolution, and Darwin a disin- genuous sciolist.” 26. Crick F (1988) What Mad Pursuit. A Personal View of Scientific Discovery. Basic Books, New York, p 140 27. Barber B (1961) Resistance by scientists to scientific discovery. Science 134:596602 28. Sacks O (2001) Uncle Tungsten. Knopf, New York, pp 104-105 29. Hook EB (2002) Prematurity in Scientific Discovery. On Resistance and Neglect. University of California Press, Berkeley 30. Dawkins R (2003) A Devil’s Chaplain: Reflections on Hope, Lies, Science and Love. Houghton Mifflin, Boston, p 48 31. Fisher RA (1932) Letter to T. H. Morgan. In: Bennett JH (ed) Natural Se- lection, Heredity and Eugenics. Including Selected Correspondence of R. A. Fisher with Leonard Darwin and Others. Clarendon Press, Oxford (1983), p 239 470 References and Notes

32. Somerville MA (2002) A postmodern moral tale: the ethics of research relationships. Nature Reviews Drug Discovery 1:316-320 33. Huxley AL (1931) Letter to R. A. Fisher. In: Bennett JH (ed) Natural Selec- tion, Heredity and Eugenics. Including Selected Correspondence of R. A. Fisher with Leonard Darwin and Others. Clarendon Press, Oxford (1983), p 220 34. Popovsky M (1984) The Vavilov Affair. The Shoe String Press, Hamden. [Stalin wanted quick results in agriculture that the slow but sure methods of the new genetics could not meet. Enter Lysenko with a vernalization ‘cure’ that was easy to market. He seized the crown and ruled for decades: “There was something mystical about Lysenko’s career, for regardless of failures, Lysenko kept his position. Despite all the promises made by Lysenko’s ‘progressive biologists’ and ‘true Darwinists,’ harvest yields in the 1930s did not increase.”] 35. Nirenberg M (2004) Historical review: deciphering the genetic code – a personal account. Trends in Biochemical Sciences 29:46-54 36. Meadows AJ (1972) Science and Controversy. A Biography of Sir Norman Lockyer. MIT Press, Cambridge, pp 209-237 37. Bennett JH (1983) Notes. In: Natural Selection, Heredity and Eugenics. In- cluding Selected Correspondence of R. A. Fisher with Leonard Darwin and Others. Clarendon Press, Oxford, p 118 38. Wren PC (1927) Beau Geste. Longmans, Toronto 39. Voltaire (1770) Letter to F. L. H. Leriche. 6th February. In: The Complete Works of Voltaire, Vol 120. The Voltaire Foundation, Banbury, 1975, p 18 [The full translation reads: “The number of wise men will always be small. It is true that it is increasing, but it is nothing compared with the number of fools and, although they say it is regrettable, God is always for the big bat- talions. It is necessary that honest people quietly stick together. There is no way their little force can attack the host of the closed-minded who occupy the high ground.”] 40. Eliot G (1874) Middlemarch. A Study of Provincial Life. Haight GS (ed) Houghton Mifflin, Boston (1956) p 613

Appendix 3 – No Line? 1. Rushdie S (2003) Step Across the Line. Random House, Toronto 2. Gould SJ (1999) Rocks of Ages. Science and Religion in the Fullness of Life. Ballantine, New York 3. Ruse M (2001) Can a Darwinian be a Christian? The Relationship between Science and Religion. Cambridge University Press, Cambridge 4. Jones HF (1919) Samuel Butler. A Memoir. Macmillan, London Prologue – To Select is Not To Preserve 471

5. Cock AG, Forsdyke DR (2008) “Treasure Your Exceptions.” The Science and Life of William Bateson. Springer, New York 6. Butler S (1880) Unconscious Memory. David Bogue, London. 7. Machiavelli N (1950) The Prince and the Discourses. Random House, New York 8. Huxley TH (1948) Selections from the Essays. Huxley. Castell A (ed) AHM Publishing, Northbrook 9. Forsdyke DR (2001) The Origin of Species, Revisited. A Victorian who An- ticipated Modern Developments in Darwin’s Theory. McGill-Queen’s Uni- versity Press, Montreal 10. Wilczek F, Devine B (1987) Longing for the Harmonies. Norton, New York 11. Crick F (1988) What Mad Pursuit. Basic Books, New York 12. Dawkins R (1986) The Blind Watchmaker. Longman, Harlow, p ix 13. Chardin PT de (1959) The Phenomenon of Man. Collins, London 14. Huxley TH (1879) The Crayfish. An Introduction to the Study of Zoology. Kegan, Paul & Trench, London, p 127 15. Butler S (1985) The Notebooks of Samuel Butler. Jones HF (ed) Hogarth Press, London, pp 59, 299 [Disraeli was also Lord Beaconsfield.] 16. Huxley TH (1896) Darwiniana Essays. Macmillan, London, pp 447–475 17. Shakespeare W (1599) Julius Caesar. In: Rowse AL (ed) The Annotated Shakespeare. Orbis, New York (1988)

Index

countermanding, 54, 300 A facilitatory, 300 for intra-strand pairing, 91 A Short History of Genetics by Dunn, menopause as an, 332 XXI of DNA to high temperature, 218 academic simultaneous, 60 cloister, 418 treadmill of, 239 discipline, 64 Adaptation and Natural Selection by field of specialization, XVI Williams, 215 haven, 4 adenine deamination, 373 ivory tower, 396 adenovirus, XIII mule, 66 agency sterility, 65 as designer, 22 suicide, 400 base composition as, 215 tie with industry, 399 causing geographical isolation, 186 tomb, 401 internal or external, 22 accent natural selection as, 56, 186, 215 as class barrier, 51 secondary information as, 57 as secondary information, 48, 139 aggregation. See heteroaggregation, as species barrier, 51 See homoaggregation base composition as, 148, 192 chaperones defend against, 333 is deeper than content, 51 entropy-driven, 321 linguistic divergence by, 148, 191 specificity of, 320 of genes, XIX, 213 temperature increases, 314, 322 of genomes, XVIII, 148, 192 aging accidents, 43 and cancer, 326 Achilles heel as a failure to repair DNA, 348 of AIDS virus, 259, 453 Butler on, 348, 422 of humans, 259 Huxley on, 422 AC-pressure, 272, 288 AG-pressure. See purine-loading action AIDS virus consciousness of, 8, 332, 415 Achilles heel of, 259 instinctual (innate), 9, 19, 349 as a low (G+C)% species, 201 adaptation copackaging of genomes of, 200 by low complexity segment, 279 copackaging signal of, 259 confined by what exists, 64 dimer linkage sequence of, 200, conserved by reproductive 259 isolation, 192 474 Index

evolutionary strategy of, 200, 453 contrasted with a ciliate, 301 flushing from reservoirs, 259 living molecules in, 11 genome of, 25, 257 organelles of, 22 latency of, 25 sophistication of, 22, 301 overlapping genes of, 261 An Examination of Weismannism by pandemic of, XIII Romanes, 16 positive selection of, 257 antibody stem-loop potential of, 256 as cross-linking agent, 321 superinfection of, 447 as steric complement, 316 therapy of, XIII, 200, 259, 399, class switching of, 290 453 holes in repertoire of, 299 alarm intracellular repertoire of, 302, 304 amplification of, 296 repertoire generation, 368, 373 by antigen-antibody reaction, 299 repertoire is host-specific, 300, 330 by dsRNA, 310, 313, 327 repertoire molded, 299 by virus, 327 repertoire purged, 299, 300 intracellular, XIX, 303 six steps in production of, 298 universal, 413 strength of antigen-binding by, 300 Alexandria, library of, XI, 57 variable and constant regions, 302 allele variable genes for, 299 and recombination repair, 209 Y-shaped, 302, 321 biallelic expression of, 330 antigen conflict, maternal-paternal, 371 as a moving target, 200, 328 conversion of, 210 as a not-self marker, 298 definition of, 156 as a self marker, 309 one pair insufficient, 352 at pathogen surface, 138, 282, 299 allopatry, 164, 173, 186, 393 cryptic, 316 altruism intracellular, 302 by virus-infected cell, 302 paternal in embryo, 298, 300 Darwin’s problem with, 306 antigenic determinant amino acid as a not-self marker, 298 as building block, 20, 49, 322 introduction of the term, 322 as placeholder, XIX, 237, 245, anti-recombination 266, 272, 277, 279 activity not localized, 352 basic, 134 and multiple alleles, 353 hydrophilic, 135 as key to speciation, 351 hydrophobic, 135, 272 keeps DNA intact, 214 in AG-rich gene, 239, 243, 245 apoptosis in AT-rich gene, 134, 189, 226 in multicellular organisms, 304, in GC-rich gene, 134, 189, 226 331 letter code for, 133 in protozoa, 301 names of, 49 role of mitochondria in, 126 not optimum for protein, 105, 189 triggering of, 333 one-step mutation subsets, 135 archaea, 114, 217, 249, 270 repeats. See repeats Aristotle, 5, 47 substitutions, 142 arms race amoeba. See protozoa and complexity, 332 Index 475

between predator and prey, 254 reproductive, 51, 179 intracellular, 304, 366 retained in retrovirus, 200 limits exon structure, 256 successive, 51, 165, 199, 205, 215 not for speciation, 149 temporal, 173 with forgers, 44 three fundamental isolating, 161, arrangement 185 as source of meaning, 168 to demarcate information, XVII linear, of pangens, 16 to development. See hybrid of body parts, 131 inviability of chromosome constituents, 167 to development falls, 163, 164 of elements, 6 to gametogenesis. See hybrid of facts, 24 sterility of molecules, 17 to pathogen, 303 phenomenon of, 18, 381 to recombination, occurs first, 214 autoimmune disease to transmission falls, 163, 164 due to AIRE deficiency, 309, 330 to transmission trumps others, 162, female susceptibility to, 359 163, 173 microbial equivalent of, 366 base. See pairing of brain, 329 cluster of. See base cluster when self read as not-self, 299, 304 combinations of two from four, Avery, O, 168 271 Avicenna, XX, 386 complementary duplets, 73 complementary triplets, 73 B composition. See base composition conserved (evolving slowly), 138 bacteria. See Escherichia coli deaminated, 345, 368, 373 codon position plots for, 226, 240 departure from equifrequency, 271 CRISPR defense system in, 317 methylated, 92, 345, 363 bacteriophage mispairing, 342 defense strategy of, 366 non-conserved, 138 detected as not-self, 317, 364 non-Watson-Crick pairing of, 342 microisochores in, 211 order of. See base order paradox of, 94 stacking of, 31, 35, 101, 106, 136, replication of genome of, 118 314 Baisnée, P-F, 85 substitutions, 135, 255, 259, 342 Ball, A, 94 symbols for, 30 barrier trade-offs between, 242, 245 gene subsets determining, 162, 173 unusual in DNA, 342, 345, 363 linguistic, 51 unusual in tRNA, 92 need to breach, 53, 64 base cluster of hybrid inviability. See hybrid and purine-loading, 113 inviability and transcription direction, 112 of hybrid sterility. See hybrid as cluster of clusters, 112 sterility level of selection for, 122 placental, 298 violation of PR2 by, 112 postzygotic, 162 base composition prezygotic, 162 476 Index

adoption by transposed gene, 120, character of the man, 398 206, 208 character units of, 17, 56, 178 and growth temperature, 246 detractors of, 392 as basis of reaction pattern, 356 disagreement with Darwin, 8, 392 average for a species, 226 on Butler, 8, 16, 154 correlation with recombination, on complementary factors, 179 150 on discreteness of species, 58 dependent component of CG on enzymes, 17 frequency, 369 on genetic factors, 17 dependent component of stem-loop on religion, 416 potential, 96, 100, 199 on residue concept, 178, 184, 191 dependent message, 411 on sex and speciation, 354 determines n-tuple frequency, 80 on variation, 131 determines speciation, 185 photo of, 175 differences affect stem-loop Beau Geste by Wren, 400 extrusion, 197 Bechamp, A, 319 in phylogenetic analysis, 190, 200 Berkovich, S, 384 predicts folding energy, 199 Bernabei, R, 384 pressure by two bases, 271 Bernardi, G pressure on amino acid and classical isochores, 205, 213 composition by, 134, 189, 237, and genome phenotype, 142 279 bias profile for a sequence, 115 in mutation. See mutation bias same in both strands, 72 in research support, 4, 171, 399, unidentified properties of, 84 470 base order of codon. See codon bias dependent component of CG of unbalanced dice, 21 frequency, 369 Bibb, M, 211 dependent component of stem-loop binary digit, 40, 268, 411 potential, 96, 256, 283 binomial distribution, 89, 158 dependent message, 411, 413 bioinformatics. See EB determines n-tuple frequency, 80 for phylogenetics, 64, 269 bat, 41, 301, 378 gene-centered, 3, 171 Bateson, G history of, XVII, 171 influenced by father, 393 of brain function, 377, 385 on information conflicts, 222 the new, IX, XV, XXI, 3, 5, 269 on information levels, 47, 60 bird. See chicken on information theory, 267 adaptation for flight, 301, 378 on religion, 380 brain size of, 43, 54 photo of, 61 DNA content of, 41, 305 Bateson, P, 394 migration of, 9, 41, 43 Bateson, W nest-making by, 9 agreement with Romanes, 171 pigeon hybrids, 177 and the rogue phenomenon, 372 blending and wax model, 17 inheritance, 154, 174, 194 as pioneer, XIV, XVIII, 4, 166, inheritance of multigenic traits, 392, 400 158, 355 Index 477

not with sex characters, 155, 352, his frustration by Grant Allen, 469 355 his frustration by Romanes, 10, of characters, 59 395 of genes, 192, 194, 213 his need to self-publish, 400 of genomes, 201, 213 his revulsion at natural selection, Bök, C, 71 22 brain. See memory known of by Eliot, 395 ablation of parts of, 379 Lamarckian viewpoint of, 22 alteration in structure of, 20 not understood, 24, 387, 396 and consciousness, XXI, 415 on aging, 348, 422 and dreams, 21, 388 on concealing meaning, 397 as immunologically privileged, on egg and hen, 8 287, 379 on evolution of machines, 20, 467 hippocampus, 370 on heredity and memory as one, 8, laterality of, 385, 388 10, 11, 378 rapid methylation in, 465 on history, XVI size in birds, 43 on hybrid inviability, 65, 297 size not correlated with memory, on hybrid sterility, 65, 171 384, 386 on life, 21, 423 synaptic plasticity hypothesis, 379 on memory running a gemmule, 19 brain disease on natural selection, 153 Alzheimer's, 287 on non-blending of sex characters, and prions, XIII, 287 156 and protein aggregation, 287 on sexual reproduction, 52 and trinucleotide expansion, 287 on species limits, 53 autoimmune, 329 on variation as origin of species, blindsight, 388 21, 154 Huntington's, 285 on words as mere means, 385 multiple personality syndrome, 386 portrait of, 7 psychosomatic, 305 water-dipper analogy of, 373 schizophrenia, XII, 60, 386, 399 seasonal influences on, 388 C spinocerebellar ataxia, 287 cancelling Brave New World by Huxley, 399 of epigenetic states, 372 Brenner, S, XII, XIV, 446 of memories, 13 Bridges, C, 358 cancer. See paraneoplastic disease Brücke, E, 301 as lost population homeostasis, 331 Buffon, GLL, 397, 427 cells display self, 329 Bultrini, E, 84 cure of, XII, 329, 393, 399 Butler, S in post-reproductive life, 326 and language, XVII, 18 individualized response to, 328 and natural penetration, 16, 26 oncogene, 258, 326, 463 as challenger of authority, 8, 24, oncoprotein, 103, 326 417 suppressor gene, 368, 463 as friend of Theophrastus, 467 cat, 15, 27, 70 as regarded by Bateson, 8, 16 cell as shifter of perspective, 7, 388 478 Index

aggregation of, 320 his GC-rule, XVIII, 189, 205 as an elementary organism, 301 his PR1, XVII, 29 as an immune system, 302 his PR2, XVII, 72, 85, 198, 349 cycle of mitotic division of, 346 on preservation of information, cytotoxic. See lymphocyte 150 death at home or in exile, 331 PR2 compliancy in introns, 84 death by apoptosis, 304, 331 PR2, precision of, 88, 106 death by necrosis, 331 PR2, violation of, 112, 120, 125, detects subatomic particles, 382 198, 267, 288 division as alloting characters, 18, rules summarized, 265 343 Chen, J-H, 199 DNA content of, 378 chicken. See bird medullary epithelial, 330 as an egg’s way, 8, 11 meiotic division of. See meiosis color of feathers, 17 mitotic division of, 301, 346 inborn capacity of, 9 number in brain, 381 intron size differences, 42 phagocytic, 331 chromosome. See X-chromosome, population size homeostasis, 331 See Y-chromosome red blood (erythrocyte), 320 19 of humans, 79, 81 regeneration from stem, 287, 327 4 of humans, 81 cerebral accounting between, 89 alterations, 19, 20, 23 accounting within, 89 event, 307 as reaction system. See reaction wiring, 19 system CG island. See CpG island assortment at meiosis, 177, 196, chaperone. See molecular chaperone 344 character centromere, 108, 289 antigenic, 296 chromatin configuration of, 373 assortment among children, 176 conjugation by homologs, 182, blending of, 54, 355 194, 297 dilution of a new, 59 diploidy of, 38 dominant and recessive, 155 dosage compensation by, 357 inducible, 25 ends (telomeres), 108 latent. See latent genes located to, 175, 178 not transferable by breeding, 179 haploidy of, 38 recognition before classification, incompatibility at meiosis, 168, 295 177, 178, 184 sexual, 25 late replication of, 346 transferable by breeding, 179, 184 linear pattern of, 169 unit as defined by Bateson, 17, 178 mechanism of inactivation, 360 Chardin, PT, 420 meiotic division of, 183, 297 Chargaff, E mitotic division of, 175, 183 as discoverer, XVII number of, 185 difference (cumulative skew), 119 number of sterility factors on, 356 difference (skew), 89, 113 orientation, 89 difficulties of, 400, 467 pseudoautosomal region of, 356 his cluster rule, XVIII, 111, 127 repatterning of, 62, 167, 355 Index 479

telomere strand asymmetry in, 288 in mRNA, 92, 136 thread-like, 346 position plot for a gene in many transposition of segments, 185, 259 species, 230 class position plot for genes within a as blending or non-blending, 158 species, 231 as dangerous or non-dangerous, position plot for species, 227, 229 295 position plot switch-over point, as friend or foe, 295 233 as harmful or non-harmful, 299 position plots, context- barriers, 51 independent, 233 of adverse event, 43 reading frames for, 137 of genotypic change, 61 synonymous sets of, 50, 141, 205, of immunoglobulin, 290 224 of macromolecule, 19 third position, independence of, of transcript, 316 134, 226, 231, 271, 276, 278 Clausen, R, 203 tissue-specific usage of, 213 cluster of bases. See base cluster translation rate and accuracy, 116, cluster rule. See Chargaff, E 140, 202, 225 code coevolution active and passive, 222 of prey and predator, XIX, 336 as agreed convention, 19, 47, 133 of proteins in common cytosol, 326 degeneracy of, 50, 134 complementarity dimensions of, 47 between antigen and antibody, 316 for base composition, 413 between self and not-self RNA, for base order, 413 312 general or individual-specific, 413 between sterility factors, 180 linking phenotype to genotype, 18 key and lock, 30, 47, 185 needed for meaning, 47, 413 of bases, 30, 185 plasticity of, 141 of codon and anticodon, 93, 136 the genetic, 133, 400 of sword and scabbard, 185 universality of, 133 of templates, 32 codon testing for, 196 as five base unit, 136 complexity. See low complexity as three base unit, 49, 136 measurement of, 267 bias as a dialect, 225 of explanation, 417 bias as non-random, 94, 223 of psychomotor activity, 9 bias as secondary, 225 related to compressibility, 268 bias at functionally minor sites, related to entropy, 268 208 related to uncertainty, 268, 411 bias not translation-driven, 206 conflict. See information conflict bias, species specificity of, 223 between genomes, XIX, 371 coincident, 146, 442 between instinsic and extrinsic, 70 cooperation between positions of, between mRNA structure and 236 coding, 95, 103, 105 for starting protein synthesis, 134 between nucleus and cytoplasm, for stopping protein synthesis, 134, 105, 261 224 between protein and DNA, 254 480 Index

between RNA and DNA, 260 and DNA structure, XI, 29, 91, 394 resolution of, 26, 94, 221, 250 and repetitive sequences, 289 within genomes, XIX, 350 his connectionist view of memory, consciousness 379 of action, 8, 331 his questioning of natural conservation. See preservation selection, XVII, 38 as phylogenetic premise, 64 his unpairing postulate, 38, 195, low in unclassified transcripts, 316 446 not always function indicator, 306, on hybrid sterility, 64 316 Crookes, W, 14 of exon more than intron, 41 crowded cytosol of intron more than exon, 256 and volume exclusion, 458 of phenotype and genotype as conducive environment, XIX, correlated, 146 124 of stem-loop potential, 259 early appearance in evolution, 319 context restricts water mobility, 324 dependence of cues, 60 Crowther, CR, 182 independence of codon plots, 233 cytosine deamination continuity in immune repertoire generation, as unnecessary difficulty, 171 368 between man and animals, 378 in mitochondria, 126 in DNA strand synthesis, 120 non facit saltum, 203 D of genetic factors, 17 Darwin, C of germ-plasm. See germ-plasm and Lamarckism, 24, 443 of inheritance, 32 and latency, 25 of variation, 173, 184, 191 as model for Grampus, 467 conventional phenotype Butler’s commentary on, 24, 395 and natural selection, 63 caveat of, 150, 392 tracks environment, 20 difficulties of, 186, 306 versus genome phenotype, XVIII, disparaged classification, 4 51, 144, 226, 350 disparaged evolution in jumps, 203 copying his prose, XVII from a template, 32, 114 his theory of natural selection, XI, of DNA information, 20, 32, 115 22, 149, 153, 173 of pattern, 36 his theory of pangenesis, 15, 52 of vibrations, 12 his understanding of information CpG island concept, 5 and self-complementarity of CG, his work, 3, 354 345 on altruism, 306 associated with Alu, 307 on external conditions, 153 is near promoter, 367 on formative matter, 6 major and minor, 368 on human brain, 377 to identify hidden transcriptome, on language, 27 306 on material basis of heredity, 14 Crick, F questioned by Butler, XXI and brain function, XXI, 377, 388 Index 481

questioned by Huxley, 171 expected versus observed Darwin, E, 427 frequency of, 369 Darwin, F, 66 frequency and genome design, 84, Dawkins, R 368 and selfish genes, XI, 215 given methyl accent, 363 criticism of Bateson by, 392 self-complementary, 74, 82, 364 criticism of Gould by, 393 species-specific frequency of, 368 on concealing meaning, 397 table of, 74 on genes and bodies, 8 diploidy Delbrück, M, 94 and chromosomes, 38 development and protein concentration, 334 and orthogenesis, 22 as adaptation for error-detection, as expression of a program, 5, 371 43, 200, 343 as recall of memory, 8 in retroviruses, 200 Butler’s view on, 8, 10, 11, 23, 65 discontinuity fetal nutrition during, 370 definition of, 58 genes affecting, 50, 162 facit saltum, 203 genes cooperating for, 182 Huxley on, 171 hybrid inviable when it fails, 162, in DNA strand synthesis, 121 297, 351 in variation, 58, 192 Mendel’s view on, 6 language a mark of, 377 of immune repertoire, 298, 300, non-genic, 60 303, 335 of genes, 59 of language, 5, 385 of texts, 53, 57 role of formative matter in, 6 disorder role of imprinting in, 371 in our lives, 43 slow in human child, 385, 387 in the universe, 36 stress-induced phenocopies during, related to entropy, 313, 322 328 distribution switched by short lived proteins, bell-curve of, 192 327 normal, 185 unscheduled transcription in, 309 of accents in a population, 192 differentiation divergence cryptic, 356 as branching evolution, 150, 169 depends on recombination barrier, as indicator of phylogeny. See 213 phylogenetic analysis of a duplicated gene, 206 between camel and pig, 153, 164 of an isochore, 215 between genome and its proteins, of genes as microisochores, 232, 146 237 between globin genes, 206 of sex chromosomes, 356 between HIV and HTLV, 201 of sexes, 352, 354, 357 between man and primates, 378, of sexes and species compared, 385, 387 355 between mouse and rat, 142, 147 of species, 160, 238 between prokaryotes and within a species, 50, 205 eukaryotes, 211, 249 dinucleotide. See oligonucleotide between twins, 370 482 Index

controlled by genome phenotype, junk, XIX, 63, 253, 305, 306, 313 141, 146, 149, 203 long range interactions in, 349 decreased by selective sweep, 140 mapping of, 366 essential precondition for, 188, 357 melting of duplex, 314 from ancestral sequence, 138, 185, methylation inactivates X- 202, 215 chromosome, 360 more at third codon positions, 208 natural or artificial sequences, 414 thwarted by gene conversion, 206, polymerase. See DNA polymerase 208 post-synthetic modification of, 364 DNA promiscuity of, 37, 50 accent of, 49, 194 quantity control, 43 adaptation to high temperature, recombination. See recombination 218 redundancy in, XVII, 39, 40, 341, alphabet of, 28, 345, 363 356 and protein divergences compared, repair of, 32, 36, 37, 126, 132, 239, 142 253, 342, 348, 349, 367, See antiparallel strands of, 74 recombination repair archive, 4 repeats. See repeats as a binary string, 40 repetitive elements. See repetitive as a polynucleotide, 34 element as containing life history, 13 replication. See replication as digital information store, 378, restriction fragments of, 364 381 reverse and forward complements as enzyme substrate, 108, 223, 238 in, 75 as language, XIV, 49, 61 satellite, 288, 290 as living, 13 separation of fragments of, 211, breakage by sheering, 211 366 bubbles from duplex, 195 stem-loop potential in. See stem- cell content of, 378 loop potential damage, 37, 200, 342, 343, 347, strand. See strand 349 supercoiling of, 122, 197, 218, 291 depurination by acid, 111 symmetry principle, 75, 288, 364 dinucleotides in, 74, 103 synthesis. See replication discovery as nuclein, 341 terminology of repair of, 347 divergence as time axis, 142, 147 three prime end of, 73, 120 double helix model of, 31 topoisomerase, 122 duplex hemimethylation, 365 transposition, 37 duplication as rule, 38 trinucleotides in, 76 editing of, 363 uncoiling of, 95, 121 five prime end of, 73, 120 vulnerability to heat, 217 from fossils, 162 DNA polymerase G-T mismatch in, 349 collision with RNA polymerase, homostability regions in, 205 120 in sea water, 83 direction of movement of, 116 inconstancy drives protein identification of, 32 treadmill, 109, 239 origin recognition by, 116 inversion, 37, 120 repair thwarted by, 343 Index 483

DNA Structure and Function by English Sinden, 426 Cockney accent of, 48 Dobzhansky, T, 154, 166 has characteristic n-tuples, 82 dog, 15, 50, 77, 205, 238 language, XX, 48 dominance Pidgin version of, 70 degree of, 59 telegram to China, 19 versus recessive, 155, 334, 351 Tottenham Court Road, XVII dsRNA entropy as interferon inducer, 310 and water, 314 as intracellular alarm, XIX, 287, as a force, 313, 322 310, 315 as driver of chemical change, 319 dependent kinase (PKR), 310 is related to complexity, 268 formation of, 122, 123, 310, 312 temperature increases, 31, 314 in Huntington’s disease, 287 work done by, 313 Duret, L, 120 Entropy-Driven Processes in Biology by Lauffer, 313 E environment adaptation to, 22 EB. See evolutionary bioinformatics as cause of early death, 348 EBV as ecological niche, 238 as episome, 313 colocalization in, 60 latency of, 273 extreme, 216, 249 nuclear antigen 1 (EBNA1), 273 incipient species as, 188, 201 purine-loading of EBNA1 gene in, not matching species, 58 315 of host anticipated by virus, 328 editing permissive for peptide display, 327 of DNA, 363 phenocopies induced by, 335 of RNA, 373 reproductive, 142, 187 Einstein, A, 63, 395, 397, 417, 420 selects for survival, 94 elements signalling to and from, 383 hierarchical arrangement of, 16 temperature of, 245 of language, 18 total DNA from, 83 permutation of, 6 tracking change in, 4, 20 repetitive. See repetitive element twins to assess role of, 370 Eliot, G, XXI, 391, 395, 398, 401, uniformity of intracellular, 326 431, 467 enzyme embryo active site of, 138, 325 as antigen source, 298 as a machine, 19 as passive information recipient, 7 as an executive element, 16, 49 as remembering parents, 7, 52 as ferment, 16, 319 unscheduled transcription in, 309, as producer of color, 16, 334 327 cytochrome c oxidase, 229 energetics deoxycytidine deaminase, 290 of folding, 95, 116 for DNA repair, 342 of helix formation, 101 kinase as phosphate donor, 310 of rouleau formation, 321 ligase, 37, 118, 311 of supercoiling, 122 484 Index

loss of activity by aggregation, general theory of, 393 322, 334 linear, XVIII, 150, 159, 194 methyl transferase, 363 of eye, 382, 384 nuclease, 102, 364, 366 of nucleus, 249 protease, 37 of organic from inorganic, 387, purification, 319 419 restriction, 364 parallel among viruses, 145 reverse transcriptase, 316 rate and stem-loop potential, 257 ribonuclease, 311 rate of, 38, 138 RNA-dependent RNA polymerase, evolutionary bioinformatics. See 310 bioinformatics, the new solubilization of, 319 agenda of, XIV substrates and products of, 319 emergence of, XII topoisomerase, 122 founder of modern, 225 epigenetic inheritance, 347, 363 goals of, XV, 269 Epstein-Barr virus. See EBV task of, XIV, 3 Erewhon by Butler, XXI, 8 exon error conservation, 41, 256 catastrophy, 200 discovery of, 249 correction of, 28, 64, 196, 253, 341 location in DNA, 84 detection of, 28, 53 non-conservation, 255 in type-setting, 27, 168 oligonucleotide parity in, 83 error-checking size range of, 251 by non-message sequence, 253 needs redundancy, 53, 342 F not in AIDS virus, 200 facts Escherichia coli and speculation, XVI, 392 CG dinucleotides in, 369 correctness of, 398 codon position plot of, 233 Darwin as arranger of, 24 same code as man, 413 democracy of, 395 trinucleotides of, 82 new way of looking at, 171, 396 eukaryote simplest explanation of, 63, 417 codon position plot of, 235 feather definition of, 249 evolution of, 300 shares ancestor with prokaryote, pigment of, 17 211 principle, 417 evolution ferment and mankind’s future, 4, 394, 416, as enzyme, 16 423 is not itself transmitted, 17 branching, between species, XVIII, fine-tuning 150, 159, 164 narrows frame of reference, 325 classic triad of processes in, 164 of intracellular antibody repertoire, concerted, 207, 208 304 dichotomies in terminology of, 63 of molecular concentration, 45 divergent. See divergence of proteins in a common cytosol, essence of problem of, 61, 225 326, 358 from organic molecules, 3, 419 Index 485 first parity rule (PR1). See Chargaff, differences early in speciation, 191 E gene specificity of, 230 fish, 58, 305, 378 in intergenomic recombination, Fisher, R, 153, 398, 400 201 Fitch, W, 141 in intragenomic recombination, folding 356 equivalent patterns of, 116 intermediate levels confer of randomized sequence, 101 flexibility, 236 of randomized sequence pressure. See GC-pressure difference, 101 range among genes, 236 of randomized sequence mean, 101 species specificity of, 226 path followed, 116 uniformity at second codon food position, 229 anorexia nervosa, 370 uniformity at third codon position, cannibalism, 370 212, 230 has its own memory, 13 uniformity in a gene, 211 Frontali, C, 278 uniformity in a genome, 190 fruit fly viruses that cohabit greatly differ CG dinucleotides in, 369 in, 201 dosage compensation by, 359 Galton, F, XX, 14, 15, 18, 24, 52, 54, hybrid sterility in, 356 59, 221, 432, 450 paranemic pairing in, 195 gamete strand symmetry in, 82, 84 as mailbag, 52 Y-chromosome degeneration in, formation failure, 176, 182, 297, 357 350 function formation of (gametogenesis), collective as well as specific, 324 XVIII, 177, 182, 332, 344 conservation correlated with, 56 imprinting of, 371 conservation not correlated with, loss through exile, 331 57, 306 male and female equivalence, 6, 14 house-keeping, 368 quality control of, 347 loss through aggregation, 325 transfer barrier to, 162, 165 psychomotor, 9 two types in one sex, 73 relative to gene dose, 357 GC-pressure downward and upward, 226, 236, G 272 genome-wide nature of, 80, 270 G+C. See isochore, See homostability high downward in malaria parasite, regions 261, 278 as a genic environment, 206 versus protein pressure, 226 as accent of DNA, XVIII, 194 versus purine-loading, 241 as indicator of reproductive Gelbart, W, 5 compatibility, 190 gemmules as preserving agency, 215 as germs, 6 controls strand pairing, 198 as organic substances, 52 differences decrease as pangens, 16 recombination, 203, 208 each run by a memory, 19 486 Index

named by Darwin, 15 restriction-modification complex, transfer from soma to gonads, 24 366 GenBank, 73, 89, 410 selfish. See selfish gene gene specific mutation rate, XVIII, 144 as a unit of antirecombination, 213 tissue specific expression of, 327 as a unit of recombination, 213, transposition of, 119, 206 352 versus species, 230 as a unit of transcription, 249 with no protein product, 360, 367 as microisochore, 233, 237, 349 Xist on X-chromosome, 367 as unit of preservation. See genetic preservation assimilation, 335 boundary of, 213, 215 code, 133 centered bioinformatics, 3, 171 disease, XIII, 60, 285 conversion, 206, 207, 209, 253, dominance. See dominance 344 drift, 132, 156, 253 coorientation, 125, 261 engineering, XIII copy-loss, 206, 207 factors carried by gametes, 17 definition of, XI, 56, 178, 214, factors interpreted as genes, 18 215, 251 fitness, 345 discontinuity of, 59 identity (twins), 370 distinctive (G+C)% of, 213, 215, linkage. See linkage 235 program, 4 dosage (copy number), 334 revolution, 150 dosage compensation, 357 texts, XI duplication of, 206, 207, 247 genetic science for courtship display, 349 attacked, 400 G-zero switch 2 (G0S2), 307, 368, classical, 64 463 launched, XVIII G-zero switch 30 (G0S30), 370, progress delayed in, 171, 392, 470 463 genocentrism, XIV, 3, 26 hitch-hiking by, 140 genome house-keeping, 346, 367 as a constellation of genes, XII incompatibilites between products as a unit of preservation, XVIII, of, 351 215 isolation before change in function, as a unit of recombination, 213 208, 238 as an information channel, XIV, 3 length in birds, 41 circular of lambdaphage, 118 length in EBV, 278 circular of SV40 virus, 119 length in malaria parasite, 262 compactness, 38, 200, 257, 273 linkage. See linkage convergence of two, 202 multicopy, 207, 208 divergence. See divergence mutator, 239 homostability. See homostability nef in AIDS virus, 447 human accelerated regions in, 385 non-allelic, 158 hypothesis of Grantham, 225 overlapping another gene, 257, 261 imprinting, 371 paradigm of, XII, 3 information content of, 40, 267, 304 Index 487

isochore. See isochore mutations in, 343 phenotype. See genome phenotype virus sequences in, 316 rebooting of, XIX, 343 germ-plasm selfish, XIX, 237 constituents of, 19 sequencing project, XII, XIV, 366, continuity of, 19, 301, 432 399 Goldschmidt, R size and strategy, 252, 332 and chromosomal pattern, 150, space limitation, XIX, 70, 221, 252 167, 191 species specificity of n-tuples in, and macroevolution, 61, 393 81 and reaction system, 167, 203 understanding of, XIII, 5, 171 character of the man, 398 uniformity of (G+C) in, 190 distinguished genes and reaction virus fragments in, 316 system, 167, 355 genome phenotype informational viewpoint of, 168 and physiological selection, 63 non-genic viewpoint of, 166 as reprotype, 51, 187 on complementary factors, 180 codon position plot as index of, on monstrosity, 203 228 on phenocopies, 328, 337 controls divergence, 146, 203 on sex and speciation, 354 multiple pressures on, 264 photo of, 62 over-rules conventional phenotype, Goldsmith, O, 381 142, 350 gonad, XVIII, 19, 24, 161, 172, 177, targeted by non-classical factors, 194, 297, 348 141, 223 Gould, SJ genotype on biohistorians, XVI as a constellation of genes, 4 on spandrels, 373 as a hierarchical element, 16 outcry against, 400 change due to pattern change, 167 supported Goldschmidt, 393 change enhances somatic versus Dawkins, XX flexibility, 61 Granovetter, M, 300 destroyed by meiosis, 214 Grantham, R, 225 plasticity of, 328 Gregory, RP, 178 primary constituents of, 19 Greig, D, 185 geographical isolation. See allopatry grouping. See selection of group Geological Evidences on the of clustered points, 410 Antiquity of Man by Lyell, 5 of elements, 14 germ. See gemmules of symbols, 47 definition of, 15 Guyer, M, 177 equated with formative matter, 6, 52 H recollections of, 9 Haeckel, E, 24 reconstructed from scratch, 12 Haldane, JBS, XIX, 350, 355, 429, within germs model, 11 468 germ-line Haldane, JS, 391 as distinct from soma, 15, 301 Hamilton, W, 386 eternal cycling of, 161 Hamming, R, 249, 253 house-keeping genes active in, 367 488 Index hand history information for, 19 as understanding, IX, XVI, 5 on deck, 309, 373 books, 400 on text, XXI misinterpretation of, XVI that weaves, 18 of bioinformatics, XVII, 171, 415 with six fingers, 21, 60, 131 of science, 391, 393, 400 haplosufficiency, 334, 344, 371 sources for, 5 Hebb, D, 379 hitch-hiking. See selection Hebert, P, 229 of fluctuation in base composition, height 206 as Mendelian character, 176 of gene, 140 binomial distribution of, 158 of papers, 57 determinants of, 156 of tuples, 107 dwarfism, 60 Holliday, R, 210, 222 multigenic determination of, 158 Homo bioinformaticus, XV, XXI, 89, normal distribution of, 174 313 of child relative to parent, 54 homoaggregation of peas, 155, 444 as defense mechanism, 328 of race, 159 as like with like, 321 unigenic determination of, 444 can inhibit activity, 322 Helmholtz, HL, 397 can promote activity, 322 heredity. See inheritance physiological, 322 and memory as one, 8, 10, 22, 395 prior to degradation, 322 as fundamental principle, 7 homology search, XVIII, 195, 207, as language, 16 253, 296, 297 as transfer of stored information, 8 homostability material basis of, 14 principle, XIX Heredity Genius by Galton, 59 regions in DNA, 190, 205, 213 Hering, E, 7, 10, 18, 468 homozygote hermaphroditism, 155, 161 derivation from Greek, 156 Herpes simplex virus derivation from heterozygote, 210, base composition of, 79 344 trinucleotides in, 79 enzyme concentration of, 334, 358 heteroaggregation identical sequences of alleles in, advantage of, 326 344 as defense mechanism, 328 recessive, 351 as like with unlike, 321 Hood, L, XIV between mutated and normal Hooke, R, 397 proteins, 325 Hooker, J, 155 with virus protein, 327 host heterozygote as moving target, 328 alleles differ in sequence, 344 preimmunization of, 299 crossed with recessive, 351 stiffened defenses of, 296, 336 derivation from Greek, 156 to foreign organisms, 298 enzyme concentration in, 334 human T-cell leukemia virus returns to homozygosity, 210, 344 as a high (G+C) species, 201 Hilbert, D, 387 strategy of, 200, 313 Index 489

Huxley, A, 399, 401 view of Crowther on, 182 Huxley, J, 39 view of Naveira on, 341, 357 Huxley, TH view of Romanes on, 172 and evolution in jumps, 203 and selfish genes, 6 I criticism of Darwin by, XVIII, 171 ideas criticism of Romanes by, 174, 393 appearance before words, XVI, 5, on aging, 422 171, 386 on agnosticism, 418 as memes, 57 on experts, 410 marketing of, 65, 215, 398, 470 on purpose of life, 423 of Mendel, 57, 392 hybrid that fly, 11 between DNA molecules, 39 when novel need more time, 397 between RNA molecules, 39, 124 immune receptor discipline, XV, 64 protein, 302, 326 vigor, 64, 349 RNA, 302, 310, 317, 373 hybrid inviability immune system. See thymus, See not- and Haldane’s rule, 350 self, See self and not-self discrimination, 297 alerting of, 285, 287, 368 as a developmental barrier, 162 autoimmune regulator (AIRE) as a reproductive barrier, 165 protein in, 309, 327, 330 view of Butler on, 65, 297 EBV evasion of, 315 hybrid sterility in bacteria, 317 and cryptic speciation, 356 in jawless vertebrates, 301 and Haldane’s rule, 350 in snails, 301 as a chromosome pairing barrier, in unicellular organisms, 301 162 malaria, evasion of, 284 as a distinction in kind, 182, 186 prototypic, 300, 301 as a journey from old to new, 186 immunization as a reproductive barrier, 51, 179 against embryo, 298 as an isolating agency, 190 against self, 328 as expression of extreme prophylactic, 282, 299, 453 outbreeding, 175, 349 Impressions of Theophrastus Such, by as expression of parental Eliot, 467 incompatibility, 186 incompatibility as expression of parental between accents, 191 phenotype, 172 between gametes, 173 as expression of partner-specific between meiotic chromosomes, phenotype, 180 168, 210 as facilitator of divergence, 193 between parents, 186 as natural, 297 non-genic, 357 cured by tetraploidy, 184, 350 of pattern, 167 cycle interruption by, XVIII, 179 inflammation mule as example of. See mule extracellular, 304 view of Bateson on, 175, 179 induced by necrosis, 331 view of Butler on, 65, 171, 435 interferons and, 310 view of Crick on, 64 490 Index

intracellular, 304 syntax of, 385 information. See phenomenon of theory, 40, 236, 249, 267 arrangement trade-off between forms of, XIX, active versus passive in DNA, 222 222, 414 analog, 379, 452 use of word by Butler, 10 as held in trust, 423 use of word by Romanes, 9 channel capacity for, XIV, 414 when stored is memory, 5, 377, compressibility, 381 381 concept of, 18, 52, 341 inheritance. See blending, See conflict between forms of, XIV, heredity XVII, 69, 221, 414 discrete, 154 context of, 60 epigenetic, 347, 364 digital, 379, 452 horizontal, 160 direction of flow of, 50 Mendelian pattern of, 177 externalized mental, 383, 415 non-Mendelian pattern of, 176 holographic storage of, 384 of acquired characters. See in macromolecules, 19 Lamarck, J levels of, XVII, 49, 60, 70, 222 preformation model of, 11 limit of scope of, XVII transgenerational, 372 meaning of, 413 insect. See fruit fly measurement of, 41, 267, 411 extracellular RNA in, 315 mental, 7, 19, 48, 377, 415 firefly, 383 penetrance of, 25 flight of, 301, 378 preservation of, 21, 50, 56, 214, instinct 415 and cerebral wiring, 19 primary as text, 48, 69, 139 Romanes’ view of, 9 primary, as the conventional intelligent design, 23, 415 phenotype, 51 Intracellular Pangenesis by de Vries, primary, destroyed by shuffling, 48 16 primary, potential to carry, 254, intron 411 and conflict resolution, 250 redundant, 28, 148, 200, 221, 249 and low complexity segment, 262 regulation of expression of, 25 conserved in venom gene, 256 secondary, 48 evolution early or late?, 252, 256 secondary, as accent, 48, 139 function of, 252 secondary, as an agency, 57 in Xist gene, 360 secondary, as the genome interrupts any information, 250 phenotype, 51 length proportionate to exon secondary, impaired by primary, length, 252 139 oligonucleotide parity in, 83 secondary, not destroyed by removal of, 251 shuffling, 48 tends to pyrimidine-load, 262 secondary, potential to carry, 254, isochore 411 as genome sector, 190 statistical analysis of, 54, 405 as intragenomic isolator, 205 symbolic representation of, 6, 10, as macroisochore, definition of, 385 213 Index 491

as microisochore, definition of, acceptance by Galton, 432 213 acceptance by Haeckel, 24 hitch-hiking by, 206 acceptance by Spencer, 24 micro, as a genic GC-niche, 236 and inheritance of acquired micro, differentiation of, 232 characters, 23, 60, 316, 363, 372 origin of, 206, 211, 213 evidence supporting, 433 Landauer, TK, 381 J language acquisition by child, 70, 385 Jenkin, F allied, 48 his sphere of variation, 54, 159 as metaphor, 18, 27, 72, 139 questioned natural selection, 59 as uniquely human, 377, 385 Johannsen, W confusion by, 397 and mathematics, XV convergence of, 48 and the word gene, 56 divergence of, 48, 148 and words phenotype and like a biological species, 5, 27, 148 genotype, 17 n-tuple frequencies in, 82 pure lines of, 55, 159 of genes, 48, 61 Jurrasic Park by Crichton, 163 sign, 383 spoken, 13, 51, 139, 383, 411 K syntax of, 385 Kandel, E, 380 textual, 383 Kant, I, 391 Lankester, ER Kantsaywhere by Galton, XXI citer of Hering, 468 Kimura, M, 95 critic of Romanes, 393 kissing Lashley, K, 379 as metaphor, XVIII, 196 latent between loops, 93, 123, 195, 201, AIDS virus, 25, 313 210, 259 character, 24 between tRNA and mRNA, 92, part, contrasted with patent part, 24 136 phenotype unmasked, 333 between Xist and Tsix, 360 prions, XIII entropically driven, 314 sterility factors, 180 favored by crowded cytosol, 314 Lauffer, M, 313, 322 in chromosome pairing, 195, 196 Le Bourgeous Gentilhomme by inhibition by purine-loading, Moliere, 70 XVIII, 312 letter Kleckner, N, 195 alphabet of, 16, 381 Koëlreuter, JG, 14 base as, 34 Kornberg, A, 32 chromosome as carrier of, 168 Krisch, H, 107 fifth, 363 frequency in a language, 48 L in print block, 13, 168 permutated, 168 Lamarck, J shuffled, 48 acceptance by Butler, 23 unread in mailbag, 52 acceptance by Darwin, 443 Lewes, GH, 10, 431, 467 492 Index

Lewontin, R, 373 in Victorian times, XX, 7, 12 life persistence of, 421 as memory, 21 low complexity segment. See repeats as phenomenon, 47, 319 abundant at G+C extremes, 270 difference from non-living, 13, 419 and purine-loading, 262, 282 history in DNA, 13 as simple sequence, 262, 269 how to live it, 417 correlates with base A, 278 origin of, 378, 382, 387, 419, 452 correlates with surface domain, limit 284, 304 in channel capacity, XIV, 414 detected with Seg program, 274 in death style, 331 identification of, 269 in enzyme reaction rate, 334 in EBV, 273 in genome space, 70, 221, 252, in malaria parasite, XIX, 278, 282 300, 315 non-repetitive, 278, 285 in number of base permutations, role at nucleic acid level, 269, 284 127 Luck or Cunning, by Butler, 10 in protein concentration, 334 Lyell, C, 5 of a race, 54 lymphocyte of a species, 53, 184, 326 B-cell, 298 of a theme, 66, 149 cytotoxic, 322, 327, 328 of codon flexibility, 94, 134 holes in repertoire of, 336 of concentration of a positive selection by near-self, 336 macromolecule, 45, 320, 324 repertoire molded by self, 329, of education, 54 330, 460 of gene flow, 184 T-cell, 201, 309, 328, 459 of natural selection, 149, 377 Lysenko, T, 400, 470 of range of discourse, 71 of scope of information, XVII M of somatic flexibility, 61 Machiavelli, N, 418 of the simple, 63, 417 macroevolution, 62 of variation, 21, 58, 153, 350 macromolecules of what the mind can conceive, as enzymes, 108 215, 355, 380, 382, 386, 391, assembly from subunits, 20 398, 470 Bateson’s factors as, 18 line crowding of, 319 absence of, 424 fine-tuning of concentrations of, 45 arrangement of germs in a, 450 functions of, 19, 303 between fact and speculation, XVI, informational, 18, 20 392, 394, 418 self and not-self, 43 horizontal or tilted, 409 transience of some, 37 linkage turnover of, 37 facilitates hitch-hiking, 140 macromutation of cooperating genes, 352, 366 limited power of, 132, 185 of isochore to gene, 206 types of in DNA, 354 Little, P, XIV magnetism, 30, 186, 382 locus poenitentiae, 52, 435 malaria parasite London Index 493

circumsporozoite protein of, 282 as stored information, XVII, 5, 12, codon position plot of, 235 21, 378, 465 haploidy of, 38 between generations, 8, 156 purines and protein length, 243 cancelling of, 13, 372 synonymous mutation in, 141 conflict between two parental, 65 Markov chain analysis, 87 extracorporal, 382 Marx, K, 8, 418 immunological, 299, 366 Maside, X, 341, 356 in extracellular immunity, 316 materialism in intracellular immunity, 316, 317 of Butler, 23 in savants, 381, 388 of Crick, 377 long term, XX, 378, 382 of Hering, 8 magnitude of, 381 of Spencer, 14 many modes of, 21 Materials for the Study of Variation of parents, 7, 52 by Bateson, 17, 58, 174 remote, as in cloud computing, 383 mathematics and biology, XIV, 89, runs a gemmule, 19 175, 410 short-term, 384, 386 Matsuo, S, 208 unconscious, 9 Mayr, E, 154, 393 Mendel, G McCarthy, J, 383 and pea breeding, 154, 351, 444 meaning and the academic cloister, 418 as abstract entity, 48 as a discipline-crosser, 64 general, of codon position plots, Bateson’s advocacy of, 4, 175 233 cited by Romanes, 444 of a group of symbols, 47 ideas of, 57, 392 of a message, 60 laws of, XI, 59, 177, 392 of information, 413 ratios of, 158, 176 ultimate, XXI view on development, 6 medium menopause, 332 as a phosphate-ribose chain, 33, 70 Mental Evolution in Animals by as paper, not message, 34, 70 Romanes, 9 meiosis message. See information cell division during, 183, 347 address of, 385 chromosome pairing in, 194, 202, as a letter sequence, 70 297 as pattern, 33 failure of, 162, 177, 178, 179, 194, as written on a medium, 33, 383, 198, 297, 344, 349, 350 413 specific to gonad, 175 classifying, 60 template-critical outcomes of, 344 erased (cancelled), 62 three steps in, 343 material basis of, 385 melanin, 25, 328 may exist without meaning, 413 memory. See brain meta, 60 and heredity as one, 8, 10, 22, 395 primary, 48, 60 as a process, 21 secondary, 48 as phenomenon of arrangement, simple, for marketing, XII 18, 381 syntax of, 385 metagenomics, 83 494 Index metaphor. See language resident intracellular, 303 accent as, 191 turnover of, 37, 422 can mislead, 62, 64 vibration of, 13, 30 from computer technology, 381 Morgan, TH, 398 from money, 44 mule, 64, 65, 171, 185, 194, 297, 344, from politics, 169 435 kissing as, XVIII Muller, H sword and scabbard as, 183 and chromosome pairing, 194, 394 Method of Mechanical Theorems by and dosage compensation, 358 Archimedes, 62 and molecular vibration, 30, 97 micromutation as mentor of Watson, 34 power of, 132 genic viewpoint of, 154, 166 role in branching evolution, 185 paradox of, 358 types in DNA, 354 Müller, M, 377 Middlemarch by Eliot, 401, 429 Murray, D, 386 Miescher, JF music, 349, 388 on heredity as language, 16 mutation. See phenocopy on sex, 52, 253, 341 accepted, 11, 132, 343 photo of, 53 affects dosage compensation, 359 migration affects function and/or solubility, from equator, 25 333 of birds, 9 after reproductive life, 343 mitochondria amino acid-changing, 134 barcode in DNA, 126, 228 as a microchemical accident, 36 fusion of, 126 as a step-wise process, 135, 166, gene transposition within, 120 167, 296 good for genomes studies, 126 back, 145, 347 low in (G+C), 126 bias, 87, 225, 305, 368 maternal inheritance of, 126 buffering by molecular chaperones, negative purine-loading in, 123 333 pyrimidine-loaded RNAs of, 125 by insertion of retrovirus, XIII role in apoptosis, 126 by radiation. See radiation molecular chaperone collective, 166, 356 affects dose-response curve, 335 compensatory, 144, 146 and the heat-shock response, 333 conditional, 333 as a folding agent, 116 correlation between different types as mutational buffer, 333 of, 143 as professional interactor, 335 cryptic, 132, 174, 180, 203, 356 client proteins of, 333 effect depends on position, 138 opposes aggregation pressure, 333 forward excludes back, 145 molecules genocopy not phenocopy, 327 archaeology of, 64 gonad-specific, 172, 343 as Tekke Turcomans, 11 hotspot, 367 capable of memory, 11 in duplicated gene, 207 capable of sex, 39 lethality in homozygotes, 344 competition between, 6 lethality of second codon position, primordial, 452 135 Index 495

localized and general, 223 Nakata, A, 317 macro. See macromutation National Center for Biotechnological meltdown in retroviruses, 200, 453 Information, 73 methylcytosine to thymine, 367 natural selection micro. See micromutation and codon bias, 223 mutator genes as cause of, 239 and hybrid sterility, 186 neutral, 95, 138, 140, 223, 225, and sexual selection, 149 305 as agency, 56, 153, 159, 166, 215, non-synonymous, 134 216 path of base changes in, 135 as fundamental principle, 7, 138, phenocopy not genocopy, 309 215 pleiotropic effect of, 223, 325 as reproductive barrier, 160 proximity between two, 145 contrasted with artificial selection, rate of. See mutation rate 149 registering for later repair, 347 contrasted with physiological repair of, 132 selection, 63 spontaneous, 36, 131, 149 does not act directly on species, spread in a population, 132, 185 237 synonymous (non-amino-acid- elimination of long palindromes changing), 134, 146 by, 259 synonymous site saturation, 143, empowered by reproductive 145 isolation, 188, 194, 203 synonymous sites rarer, 143 function optimized by, XI, 94, 218 systemic, 167, 191 greater in early life, 348 transition, 135, 342, 344 level of operation of, 238, 308 transversion, 135, 344 limited power of, 58, 149 violation of neutral assumption for, preservation not guaranteed by, XI 141 questioned by Bateson, 58 vulnerability of CpG, 367 questioned by Crick, XVII, 38 mutation rate questioned by Darwin, 443 analogy with public speaking, 139 questioned by Fisher, 153 gene-specific, 144 questioned by Haeckel, 24 high in DNA recognition proteins, questioned by Jenkin, 59 239 questioned by Ohno, 84 high in viruses, 326 questioned by Pagel, 149 ratio of rates of different types, questioned by Romanes, 468 141, 146, 148 questioning of sufficiency of, XIX, synonymous sometimes zero, 141 186 temporal calibration of, 139 role in gene duplication, 206, 207 Muto, A, 226 Nature and nurture, XX, 370 N not prescient, 252, 372 Naudin, C, 155 Nägeli, C Naveira, H, 341, 356 and orthogenesis, 22 near-self on material basis of heredity, 14 as a subset of not-self, 296 on mechanism of heredity, 6 contrast with ‘altered self’, 336 496 Index

discrimination from self, 325 O primes positive selection, 336 Occam, W, 19, 63, 417 negative selection Of Molecules and Men by Crick, 380 impairs reproductive success, 138 Ohno, S, 71, 84 in exons, 42 Olby, R, 446 in generation of immune oligonucleotide. See trinucleotide, See repertoire, 299, 330 dinucleotide nematode worm derivation from Greek, 80 chromosome accounting in, 89 frequencies in phylogenetic recombination in, 195 analysis, 82 strand symmetry in, 84, 107 hierarchy in a species, 83 telomeres of, 289 overlap, 107 Neumann, J von, 381 parity is primary, 85 Newton, I, XVI, 394, 397 relationship between orders of, 82, Nirenberg, M, 400 85, 368 not-self reverse complements in introns, 84 detection of, 325 tracts or runs, 111 includes the near-self subset, 296 organelles. See mitochondria, See recognition of nucleic acid as, 303 amoeba Novella, I, 145 organism nucleotide. See oligonucleotide as a microcosm, 6 as building block, 33, 115 computation of, XIV structure, 33 elementary, 301 nucleus reconstruction from DNA, 163 archival type in ciliates, 301 variant, 131, 149, 187 as defining eukaryote, 211, 249 Orgel, L, 289 chromatin threads in, 16 origin evolution of, 249 multiple for replication, 118 recombinational isolation in, 202 of human mental power, 378 selection pressure differs from of life, 378, 387, 419 cytoplasmic, 105 of replication, 116 S-phase volume doubling of, 346 of species. See origin of species working type in ciliates, 301 of variation as origin of species, number 154 and meristic variation, 131, 158 origin of species and parity, 71 as a physiological question, 15 of allelic pairs, 159 as interruption of reproductive of brain cells, 381 cycle, 350 of branch points, 149 equated with variation, 21 of chromosomes, 185 essence of problem of, 161, 179, of genes affecting development, 184, 186 162 like origin of sex, 354 of sexes, 72, 341, 357 needs barrier breached, 53 of sterility factors, 356 Osawa, S, 226 of unit characters (genes), 178 ovule, 6, 14, 173 Nussinov, R, 88, 107 ovum nutshell, this book in a, 414 Index 497

and random drift, 156 properties of, 35 implantation in uterus, 332 quasipalindrome as precursor of, receptors on, 296 107 with AT-rich repeats, 259 P with trinucleotide repeats, 259 PAM matrices, 266, 453 Pagel, M, 149 pangenesis pairing extended by de Vries, 16 antiparallel, 93 extended by Miescher, 52 between A and U in RNA, 93 implies representation of parts in between chromosomes in gamete, 16 tetraploids, 202, 350 theory of, 15 between G and T in DNA, 97, 102, paper 367, 462 as medium, not message, 12, 34 between G and U in RNA, 92, 104 of Mendel, 57 between I and C in RNA, 373 paradigm between loops, 88 classical Darwinian, XXI between purines and pyrimidines, for hybrid sterility, 341 30 genic, XII, 4, 171, 358 beween G and U in RNA, 462 shift, XII, 150 chromosome barrier to, 182, 210 paradox energy values for dinucleotides, addressing of, 395, 397 102 bacteriophage, 94 failure due to pattern change, 167 GT and recombination, 290 interstrand, 91, 93 Muller’s, 358 intrastrand, 91, 106 of autoimmune disease, 329 like-with-like, 185 of stability and variability long-range, 88, 106 combined, 11 of meiotic chromosomes, 168, 177, of understanding both history and 194, 197, 297, 344 subject, 5 paranemic, 196, 210 paraneoplastic disease, 328, 329 reversal to expose bases, 38, 195 parity sense-antisense, 29, 77, 122, 360 between two lines of text, 27 sense-sense, 29 between two sexes, 72 stability numbers of Tinoco, 96 between two strands, 72, 196 strong between G and C, 96 measurement of, 268 Watson-Crick, 30, 35, 97, 185, primary at oligonucleotide level, 198, 218, 291 85 weak between A and T, 96 rules (PR1, PR2). See Chargaff, E palimpsest as a bad metaphor, 62 within one strand, 72 palindrome pathogen. See virus and inverted repeats, 107, 259 as not-self, 303 as obeying parity rule, 71, 84 death if unmutated, 138 CG as self-complementary, 364 identification from base Greek derivation of, 71 composition, 148 in humans, 259 implication of its genome size, 332 in Y chromosome, 356 preadaptation of, 328 498 Index

recruitment of host self-antigens Phillips, G, 87 by, 328 phylogenetic analysis, 64, 82, 148, resistance to heat, 216 190, 200, 269 RNA transcript as, 287 physics, XV, 94, 386, 397 strategy of, 335 physiological surface antigen of, 138 aggregation, 322 pattern complements, 188 duplication of, 36 process of information retrieval, 21 incompatible chromosomal, 168 reaction system, 168 Mendelian, 176 selection. See physiological non-Mendelian, 372 selection of genotype, 62, 167 self-destruction, 331 of methylation, 363 physiological selection of stem-loops, 198 critics of, 174 pea, 6, 154, 155, 159, 179, 372 follows collective variation, 174 Pearson, K, 400 initially cryptic, 173 Pellew, C, 372 named by Romanes, 173 Perec, G, 71 Pizzi, E, 278 periodical Planck, M, 397 rhythms, 10, 12 plant seed. See pea sequence elements. See sequence, contribution to, by gametes, 6 periodicity in development of, 8 Phaestos Disk, 5 early germinating, 173 phenocopy genetically modified, XIII distinct from genocopy, 328 memory lost when eaten, 13 no genetic change, 335 pure lines of, 55 phenomenon poetry associated with memory, 8 as an error-detecting device, XVII, of arrangement, 18, 381 70 of imprinting, 371 as unnatural, 69 of in-series redundancy, 39 Polanyi, J, 401 of life, 47 polarity of rogues in peas, 372 of biological reading, 115 paranormal, 386 of biosynthesis, 115, 120 phenotype of DNA strands, 35 as a hierarchical element, 16 of proteins, 115 as a set of characters, 4 pollen, 6, 14, 173, 176 conventional. See conventional polymorphism phenotype as a hazard, 330 determined by proteins, 49 as an individualizing factor, 328 genome. See genome phenotype due to microsatellites, 290 introduction of the term, 17 is natural, 347 not affected by sterility factors, not neutral, 328 180, 356 of malaria protein, 282, 284 plasticity of, 61, 327, 328 prevents viral anticipation, 304, sterility-of-offspring as a parental, 316 180, 186 terminology relating to, 304 Index 499 polyploidy. See tetraploidy gene as a unit of, XI, 50, 215 population genome as a unit of, 215 allele establishment in, 166 imperfections of, 26 apocalypses affecting, 348 needs a barrier, 64 bottle-neck, 138, 140, 141 needs reproductive isolation, 191 diversity lost, 141 of a gene duplicate, 208, 245 expansion of, 254, 319 of an isochore, 206 homeostatic regulation of size of, of ancient texts, 57, 62 331 of hybrid sterility, 186 purging of bad genes from, 345 of information, 21, 56, 214, 415 variation within, 191 of structural element in protein, variation within subset, 174 260 positive selection of words, 27, 172 for evolution of dosage pressure compensation, 358 definition of, 272 for immune receptor function, 326 for aggregation, 323 for improved venom, 255 general and local, 264 metaphor for, 254 summary of, 264 of a malaria gene, 282 principle component analysis, 81, 83, of immune repertoire, 317, 335 409 of species as a group, 187 Problems in Genetics by Bateson, 17 promotes reproductive success, process 138 cyclic, 161 role of codon position in, 208 evolutionary, 58, 420 to react with near-self, 299, 336 mental, 21 power new, from triad to tetrad, 164 inborn, 9 of discovery, 5, 470 of assuming a character, 16 of heredity, 7 of hereditary transmission equal in program sexes, 6, 14 for an enzyme, 19 of recalling memory, 24 for cell death, 126 to cause is transmitted, 18 genetic, 4 to destroy a pigment, 17 of embryonic development, 5 to invoke character is transmitted, prokaryote 17 archaea as, 217 to vary beyond Jenkin's sphere, 59 bacteria as, 211 Prabhu, V, 75 definition of, 249 predator shares ancestor with eukaryote, external and internal, XIX 249 of deer, 153 promoter of rodents, 254 differential methylation of, 371 preservation. See conservation RNA polymerase binding to, 116, as more fundamental than function, 251, 308, 367 XI, XIX, 57, 214 protein as precondition for selection, 57, active site of, 106, 138 208, 392 aggregation in brain disease, 287 by secondary information, 50 antigenic determinant of, 322 500 Index

as a mini-molecular chaperone, ORF encoding a, 137 335 peptide chain in, 93 as an aggregating agent, 323 plasma, 320, 321 as an amino acid chain, 49 polarity of, 115 as an enzyme, 49 pressure. See protein-pressure as an executive unit, 25 primary function of, 305, 326 as an immune receptor, XIX, 302, rhodopsin, 384 326 secondary functions of, 305, 326 circumsporozoite, 282 sequence alignment gaps, 266 coaggregation with unrelated sequence alignment scoring, 265 proteins, 287, 325 solubility of, 285, 319, 324, 333 collective functions of, 321, 323, species invariancy of, 228 359 specific activity of, 324 complexity of, 270 surface hydrophilic, 284, 304 concentration fine-tuning of, 324, synthesis favored by purine- 325, 333, 358 loading, 315 concentration is independent of synthesis inhibited by dsRNA, 310 cell sex, 359 synthesis of, 49, 93, 134, 140 defeats DNA, 260 turnover, 36, 322 degradation to peptides, 322 variable parts of, 258 denaturation, 322 protein-pressure divergence versus genome dominance of, 260 divergence, 146 extreme in overlapping regions, DNA recognized by, 222 261 domain swapping, 253 for function, 237, 284 domain, functional, 262 on codons, 202, 226, 228, 237 domain, non-functional, 284 versus DNA, 254 domain, structural, 245 versus GC-pressure, 226, 231 element, structural, 260 versus purine-loading pressure, evolution after RNA, 253 239 factors determining concentration versus RNY-pressure, 137 of, 324, 358 proteosomes, 327 fellow travelers of, 324 protozoa flexibility to change, 105, 142, 228 amoeba. See amoeba for peptide-display, 322, 327 conjugation in, 301 functions other than its specific, sophistication of, 301 303, 326, 458 Tetrahymena, 190, 301 heat-shock, 202, 309 purine-loading histone, 373 and base clusters, 113 interdomain space is for simple and optimum growth temperature, sequence, 272 218 interdomain space is less in as dominant pressure on protein thermophiles, 246 length, 281, 287 length affected by base as inhibitor of kissing, XIX, 123 composition, 243, 244, 262, 281 in bacteria, 240 major histocompatibility complex in EBNA1 gene, 273, 277, 315 (MHC), 322, 336 in malaria parasite, 279 Index 501

in thermophiles, 114, 218 fluctuation in base composition, inversely related to (G+C)%, 126 206 location in loops, 113, 122 forces produce parity, 72 negative in mitochondria, 123 generation of antibody repertoire, placeholder amino acids support, 298 243 genetic drift, 156, 253 to self-discriminate, 312 inactivation of X-chromosome, versus fold pressure, 282 357 versus GC-pressure, 241 interactions between DNA bases, versus protein-pressure, 239, 240 198 versus RNY-pressure, 137, 239 mixing of base letters, 96, 99, 101 ways to achieve, 272 mutation as, 134, 347 wide distribution among species, position of a dice, 21 123 selection for sequencing, 410 pyrimidine-loading turning of stones, XVI by EBV, 273, 313 usage of codons, 225 by HTLV1, 313 Ray, J, 182 in mitochondria, 125 reaction system in some viruses, 127 as a unit of recombination, 445 rare in bacteria, 239 Clausen's concept of, 203 is different from genes, 167, 355 Q sex chromosomes as example, 355 recombination. See anti- question recombination, See homology chicken-and-egg type, 119, 269, search, See gene conversion 270 adaptive value of, 200, 253 horse-and-cart type, 85 as destroyer, XII, XIX, 201, 207, of genic and non-genic causes, 185 214, 366 of mind and brain, 380 benefits of lost, 352 ultimate, XXII, 377 between X and Y chromosomes, 352 R correlation with base composition, race 150 and phenotypic differentiation, 355 cut first model for, 195 as a long-lived individual, 54, 348 gene as a unit of, 213 as a variety, breed or line, 355 genome as a unit of, 213 cross between different, 355 homostability regions support, 205 habitual actions of, 9 hot spots, 215, 290 radiation, 22, 25, 36, 216, 327, 382 illegitimate, 259 random intergenomic, 205 assortment of chromosomes, 156, intragenic, 284 343 intragenomic, 205, 206 element at higher oligonucleotide less when selection is positive, 140 orders, 87 of DNA segments, 37 events, 27, 43 pair first model for, 195 recombinator sequence for, 221, 222 502 Index

repair by means of, 253, 344 in a Y-shaped fork, 34, 117, 120 repair, as last court of appeal, 348 origin of, 116 significance for evolution, 38, 208 termination of, 118 somatic, 290 reproduction trade-off with length, 273, 278 as a cyclic process, 161, 350 reductionism, XXI, 32, 64, 377, 380 as revealing memory, 8 redundancy asexual, 9, 350 four-fold, 39 of habits, 9 in codons, 134, 141, 205, 223 sexual. See sexual reproduction in mitochondria, 126 reproductive isolation in-parallel, 28, 343, 345 allopatric, 164 in-series, 39, 343, 356 as conserver of adaptations, 192 needed for error-detection, 53, 342 as origin of species, XVIII, 164, two-fold, 39, 342 179 Reese, V, 347 as potential species multiplier, 238 regeneration as precondition for divergence, 191 by recycling, 37 between camel and pig, 164 of archival nucleus, 301 between strains of Tetrahymena, of lost cells, 287, 327 190 of phenotype from genotype, 8 by chromosomal incompatibility, of plant from cuttings, 6 196 regression to the mean, 54, 159 by developmental barrier, 164 repair. See DNA, repair of by hybrid sterility, 164 repeats. See low complexity segment by transmission barrier, 164 and speciation, 289 defined, 51, 159 copy number of, 106 empowers natural selection, 194, direct, 260 203 distinct location in exons, 260 first manifest in offspring, 180 inverted. See palindrome partner-specific, 172, 194 length of, 106 role of repetitive sequences in, mirror, 259, 426 289 opposing stem-loop potential, 260 role of secondary information, 50 satellite, 288, 289 secondary mechanisms of, 357 short tandem, 285 sympatric, 165 supporting stem-loop potential, reprotype, 51, 63, 187, 196, 198, 349, 260 425 repetitive element research Alu, 306, 368, 373, 379 bubble in, 398, 399 as variation-generating device, 315 decoys in, 303, 306, 313, 433 discovery of, 40, 306 marketing of, XII, 394, 398, 470 editing of, 379 priorities in, 3, 4, 171, 380, 399 fewer in birds, 42 refocusing, 341, 377, 380, 396 near G0S2 gene, 307 retrovirus. See human T-cell leukemia replication virus, See AIDS virus bidirectional, 116 ancient remnant in genome, 316 continuous or discontinuous, 121 inactivation by methylation, 367 differential timing of, 346 mutational meltdown in, 200 Index 503

phylogenetic analysis of, 200 virus, evolution of, 145 use in genetic engineering, XIII world, 253, 452 revolution RNA polymerase genetic, 150 copies template strand, 251 in ideas, 4 cryptic promoters for, 316 new bioinformatics as, XXI dedicated, 306 rhythm direction of movement of, 112 communication of, 12 promoter for, 116, 308, 367 periodical, 10 RNY rule recurrence of, 12 and overlapping genes, 261 ribosomes, 93, 125, 202, 218 and RNY-pressure, 137, 239, 272 RNA as basis for periodicity, 226 antibody, also expressing primary chemical basis of, 137 function, 309 determines reading-frame, 261 antibody, innate repertoire of, 303 pattern in both DNA strands, 137 double-stranded. See dsRNA to detect protein coding, 137 editing of, 105, 315, 373 violated by AG-pressure, 138, 239, hidden transcriptome, XIX, 306, 279 315, 316, 327, 368, 373 Romanes, G immune receptors, XIX, 302, 311, alliance with Sanderson, 391 315 and holy grail, 190 induced silencing complex (RISC), and intrinsic peculiarity, 191 310 and the term "ultra-Darwinian", interference (RNAi), 311 468 low copy number types, 306 as pioneer, XIV, XVIII, 174, 392 molecules driving on same side, cited Mendel, 155, 444 125 conflict with Butler, 10, 19, 62, mRNA, 93, 95, 250 387, 395, 467 mRNA heterogeneity, 303 his collective variation postulate, mRNA structure, 94, 103 174, 185 mRNA, prediction of existence, his fruitless pangenesis studies, 24 396 known by Eliot, 395 mRNA-tRNA interaction, 92, 125, on hybrid sterility, 172 202 on instinct, 9 non-protein-encoding, 115, 251, on pangenesis, 16 261, 360, 367 on physiological selection, 63, 173 purine-loading of. See purine- on transition of germinal loading substance, 18 rRNA as most abundant RNA type, on Weismannism, 16, 154 93, 122, 396 parallels with Gould of, 393 rRNA has high (G+C) in photo of, 172 thermophiles, 218 Rosetta Stone, 5 rRNA precursor with spacer, 249 rouleau short interfering (siRNA), 310 formed in polymerized albumin, test-tube synthesis of, 39 320 tRNA, 92, 202 like a pile of coins, 31, 101, 320, versus DNA, 260 450 504 Index

like stacked DNA bases, 31, 101 non-genic, 150 specificity of formation of, 320 of group, 164, 187, 308 Rushdie, S, 415, 419, 423 of kin. See altruism Russian doll model, 11, 16 physiological. See physiological selection S positive. See positive selection with wisdom, 401 Salser, W, 94 self. See not-self, See near-self Sanderson, JB, XI, 391, 429 aggregation with self, 320, 323 Sanger, F, XII defined afresh each generation, Saunders, E, 159, 175 300 Schaap, T, 222 discrimination from near-self, 44, Schrödinger, E, 18 325 science discrimination from not-self, 44, and religion, 386, 415 295, 325, 366 and the arts, two cultures, IX, 380, discrimination, intracellular, 299, 388 300, 302, 310, 321, 359 Arabic, 386 marker in DNA, 364 authority in, 215, 417 selfish gene citation of, 418 and contraception, 332 confusion in, XX and gametic imprinting, 372 diffidence in, 418 and the menopause, 332 fiction, 386, 420 as autonomous entity, 144 hazards of technology, 3 as unit of self-preservation, XI history of, 391, 400 conflict with selfish genome by, literature, 391, 393, 400 XIX, 237 nature of observation in, 417, 419 explains altruism, 302, 308 nest-making in, 417 explains junk, 306 politics of, XX, 4, 391, 470 explains repeats, 289 research in. See research Huxley on, 6, 422 rules of thumb of, 417 sequence scope of, 415, 418 alignment analysis of, 269 specialization in, XVI, 435 ancient, 63 second parity rule (PR2). See complexity of. See complexity Chargaff, E crossover hotspot instigator (CHI) selection in, 290 and preservation, XI decomposition into dinucleotides, artificial, 149 102 as a "sweep", 140 microsatellite, 288, 290 by non-classical factors, 141 periodicity in, 226, 285, 290 frequency-dependent, 73 redundancy. See redundancy genic for survival within species, simple. See repeats 150 simple defined, 262 hierarchical theory of, 393 spacer, 249 level of operation, 85, 88, 95, 237, spurious alignments of, 269 261, 269, 308 statistics of, 405 negative. See negative selection tagging as suspect, 347, 372 Index 505 sex competition for, 70, 273 chromosomes. See X- and Y- conflict with redundancy, 28, 38 chromosomes extracellular within skin, 302 differentiation like species within genome, XIV, XIX, 70, differentiation, 354 221, 252, 300 early origin of, 253 spandrel. See water-dipper heterogametic, 350, 352, 356 speciation homogametic, 352 and repetitive sequences, 289 in protozoa, 301 driven by accent change, 51 molecular, 39 driven by synonymous mutations, sterility affects the heterogametic 148 first, 350 gene, 166, 239 two in a species, 73, 341, 357 holy grail of, 190 sexual reproduction need for prior isolation, 149, 186 ancient origin of, 254 non-genic, XVIII, 166 as a fragmenter of genomes, 214 species biparental, 9 allied, 51, 58, 176, 179, 201, 297 leads to homology search, 296 arrival, 150, 154, 161, 187 permits sequential correction, 347 as a unit of antirecombination, 214 reason for, 52, 341, 350 barcode for, 228 Shakespeare, W, XIII, 53, 57, 149 definition of, 150, 188 Sharp, P, 142 discontinuity of, 58 Shaw, GB, 51, 396, 469 discreteness of, 58 sheep, 48, 153, 154, 295, 329 foreign, 297 shuffling incipient, 164, 187, 194 sequences, 80, 95, 103, 140 selection as group selection, 187 to destroy base order, 96 sibling, 50 to destroy letter order, 48 specific codon usage, 225 Simon, J, 15 specificity of n-tuple values in, 81, Sinden, R, 31 148 skew analysis. See Chargaff versus genes, 230, 233, 236 difference analysis Spencer, H, 10, 14, 22, 24 skin spermatozoon, 14, 156 as perimeter, 302 compactness of, 38 cell death, 331 seen as self, 296 cells and radiation, 25 two types in human males, 351 pigmentation, 25, 304, 328 stacking of bases, 35, 101, 106 Smith, A, 401 stem-loop extrusion Smith, JM, 393 affected by base composition, 197 Smithies, O, 112 affected by base order, 196 soma asymmetrical, 288 as disposable, 161, 348 favored by negative supercoiling, as distinct from germ-line, 16, 175, 95, 122 301 favored entropically, 314 limited flexibility of, 61 from DNA, 97, 196 space generates mismatches, 349 between protein domains, 245 symmetrical, 107, 196 506 Index stem-loop potential recorded in data bases, 73 as flap in single strand, 74 RNY pattern in both, 137 base composition-dependent, 198 separation and annealing, 40 base order-dependent, 255 symmetry in folding energy, 107, calculation of, 96 288 conserved in AIDS virus, 259 symmetry principle, 77 conserved in intron, 256 unpairing, 195 factors affecting, 198 winding, 95 of EBNA1 simple sequence, 277 strategy widely distributed, 96 evolutionary, 54 Step Across the Line by Rushdie, 415 for accurate information transfer, Steps to an Ecology of Mind by 28 Bateson, 60 for detecting forgery, 44 sterility. See hybrid sterility for detecting not-self, 44, 368 cryptic factors for, 180 for purine-loading, 272 factors fail to complement, 180 of host versus pathogen, 300, 333, genic, 165, 177 336 non-genic, 166, 176 of predator, XIX sporadic, 178 of recycling, 37 stirp, 432 of repair, 37 stone of species-specific coding, 225 as a word, 10 of virus, to evade defenses, 200, in species wall, 187 310, 313, 317, 328, 335, 366 positions of stability of, 59 stress which to turn?, XVI and the heat-shock response, 333 storage at a critical developmental stage, extra-corporal, 382 335 holographic, 384 increased transcription in, 309, 330 of information, 21, 381, 465 structure strand and conflict, 103, 245, 260 antiparallel in DNA, 35 calculation of secondary, 96 asymmetry in folding energy, 288 domains of, 245 breakage at genic boundary, 216 mediated homology recognition, complementarity of, 185 195 displacement as loop, 210 needs of may dominate, 94, 105, guidance for error detection, 345 260 identity in density, 288 of information, 385 inward-looking, 194 of neural synapses, 379 lagging in replication, 117, 120 of oncoprotein mRNA, 103 leading in replication, 117, 120 precision in a protein, 229 migration of cross-over point, 210, primary and secondary, 70, 91 216 validation of, 102 mRNA synonymous, 114 Subak-Sharpe, JH, 84 mRNA template, 114 Sueoka, N, 87, 189, 190 non-identity in density, 288 survival paranemic pairing by, 210 of incipient species, 187 polarity of, 73 of the fittest, 22, 94, 138, 307 Index 507

Suyama, A, 205, 213, 236 The Strength of Weak Ties by sympatry, 51, 58, 393 Granovetter, 300 Szybalski, W The Structure of Evolutionary and base clustering, 112 Thought by Gould, 393 on replication origin, 118 Theophrastus, as first botanist, 467 transcription direction rule of, 122, thermophiles, 106, 114, 216, 245 284, 307 Thiselton-Dyer, W, 393 thymus. See autoimmune disease T AIRE protein located in, 309 T-cell education in, 330 task tiger, 153, 186, 187 of biology, XIV Tinoco, I, 96 of EB, XIV, 3, 26, 221 Tomizawa, J-I, 122 Tekke Turcomans, 11, 13, 432 trade-off teleology, 22, 23 between A and C preferred, 242, temperature 245 as aggregation promotor, 322 between codon positions, 243 change at ovulation, 331 between forms of information, correlation with purine-loading, XIX 218 between length and recombination for DNA degradation, 217 vulnerability, 273 of duplex melting, 31, 124, 314 between melanin and Vitamin D, of optimum growth, 218, 246 25 template between menopause and concept for copying, 32 procreation, 332 dependent reactions, 20 not of diploidy, 43 Tennyson, A, 153 transcription tetraploidy and RNA processing, 251 as cure for hybrid sterility, 184, directional polarity of, 114 350 factor acting at promoter, 367, 370 in cell cycle G2-phase, 346 failure to terminate, 308 in tobacco, 202 promiscuous, 309 text rate of, 324 ancient, 57, 62 regulation of, 122 and pretext, 416 same direction as replication, 118 genetic, XI unidirectional when genes need for complete, XIII coorientated, 125, 261 of a DNA strand, 32 unscheduled, 309 The Astonishing Hypothesis by Crick, translation. See codon 380 as rate-limiting, 202 The Birds by du Maurier, 54 efficiency of, 225 The Genetical Theory of Natural of germinal into somatic, 18 Selection by Fisher, 153 polarity of, 115 The Material Basis of Evolution by transposition Goldschmidt, 393 of chromosome segments, 185, 259 The Origin of Species by Darwin, of gene, 208 XII, 150, 153, 378 Treffert, DA, 381 508 Index trinucleotide substantive, 131 expansion mechanism, 285 summation of, 182 frequencies of, 81 unbiased, 22 table of, 76 when storage imperfect, 21 vegetative propagation, 6 U Venditti, C, 149 vibration. See periodical rhythms Unconscious Memory by Butler, 10, as memory, 12, 379 395, 427, 431 as molecular resonance, 47 universe between conformations, 97, 124, as a computer, XIV 198 dark matter in, 384 change as marker, 325 holographic, 384, 387 copying of, 12 unity of, 388 molecular, 314, 321 unseen, 377 of gene, 213, 349 Victorians, XVI, XX, 5, 6, 7, 21, 52, V 65, 396, 400, 427, 431 Vaccinia virus virus. See EBV, See AIDS virus base composition of, 72 anticipates host environment, 303, dinucleotides in, 77 316, 328 trinucleotides in, 79 as first named, 15 variation cattle plague, 14 as a character difference, 131 chemokine response to, 310 as a fundamental principle, 7 coat protein of, 94, 303, 322 by sexual shuffling, 432 coinfection by, 201, 447 collective, 172, 174, 185 cowpox, 72 continuity at genotype level, 203 evolution of, 145, 201 continuity of, 173, 191 hepatitis C, 259 cryptic, 173, 174, 203, 356 infection as stress, 308 decreased by positive selection, infection during pregnancy, 309, 140 327 discontinuity at phenotype level, interferon response to, 310 175, 203 latent, 313 discontinuity of, 59, 192 origin of, 301 discrete, 21 rubella, 309 due to nurture, 55 smallpox, 15, 72 fine gradations in, 21 strategy of, 303, 310, 312, 317, homeotic, 131 326, 328, 335, 366 intrinsic versus extrinsic origin of, superinfection, 201 173, 176 tobacco mosaic (TMV), 322 Jenkin’s sphere of, 54 vitamin D, 25 limits of its scope, 21, 55 vitiligo, 328 meristic, 131 Voltaire, 401 spontaneous, 21, 149, 173 Vries, H de sporadic, 174, 185 hierarchical elements distinguished statistical analysis of, 54, 405 by, 16 named gemmules as pangens, 16 Index 509

W coining of, 5, 172, 305, 322 difference in active and passive Wada, A, XIX, 205, 213, 233, 236, code, 222 349 meaning of, 5, 313, 363, 364 Wahls, W, 290 misprint of, 168 Wallace, AR, 23, 154, 377, 385, 393, n-tuple frequencies of, 82 468 rhyming, 388 Wan, H, 269 stone as a, 10, 385 water structure of, 30 dipper analogy, 373 worm. See nematode worm ordering of molecules of, 101, 319, marine, 252 322 Wyatt, G, 29, 394 Watson, J, XI, 29, 394 wax model, 17 X Weaver, I, 370 Weiner, BM, 195 X-chromosome Weismann, A extra product dose in females, 357 and the germ-line, 15 heteromorphy with Y, 354 and theory of germ-plasm, 17, 301 homomorphy with Y, 352 and translation of germ, 19 in ovum, 73 as Darwinist, 154, 468 in spermatozoon, 73, 351 Butler’s disagreement with, 23 in successive male and female Weldon, R, 175 cells, 358 Wheeler, J, 387 inactivation by methylation, 367 White, H, 95 meiotic pairing of, 297 White, M, 393 mutations affecting dosage Williams, GC compensation, 359 and definition of gene, XI, XIX, transposition with Y changes 37, 214, 216 (G+C), 208 and selfish genes, 144 on recombination and sex, 253 Y window as segment in a sequence, 48, 212 Y-chromosome counting bases in, 49, 198 confers maleness, 351 moving, 114 degeneration of, 357 of time, 422, 447 in a succession of male cells, 358 size optimum, 115 in spermatozoon, 73 Winge, Ö, 184 meiotic pairing of, 297 Wolfe, K, 142 pseudoautosomal region of, 208, Wolfe, V, XXI 356 Wootton, J, 269 Yomo, T, 84 word after idea, XVI, 5, 18 Z as a handle, 7, 305, 385 Zuker, M, 96